Inhibitors of E1 Activating Enzymes

ABSTRACT

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 13/828,953, filed Mar. 14, 2013, which is a divisional of U.S.patent application Ser. No. 13/526,946, filed Jun. 19, 2012 (abandoned),which is a divisional of U.S. patent application Ser. No. 11/700,614,filed Jan. 31, 2007, which issued as U.S. Pat. No. 8,207,177, and whichclaims priority under 35 U.S.C. § 119(e) to U.S. Provisional ApplicationNo. 60/764,487, filed Feb. 2, 2006, all of which are hereby incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to compounds, compositions and methods for thetreatment of various disorders, particularly disorders of cellproliferation, including cancers, and inflammatory disorders. Inparticular, the invention provides compounds which inhibit the activityof E1 type activating enzymes.

BACKGROUND OF THE INVENTION

The post-translational modification of proteins by ubiquitin-likemolecules (ubls) is an important regulatory process within cells,playing key roles in controlling many biological processes includingcell division, cell signaling and the immune response. Ubls are smallproteins that are covalently attached to a lysine on a target proteinvia an isopeptide linkage with a C-terminal glycine of the ubl. Theubiquitin-like molecule alters the molecular surface of the targetprotein and can affect such properties as protein-protein interactions,enzymatic activity, stability and cellular localization of the target.

Ubiquitin and other ubls are activated by a specific E1 enzyme whichcatalyzes the formation of an acyl-adenylate intermediate with theC-terminal glycine of the ubl. The activated ubl molecule is thentransferred to the catalytic cysteine residue within the E1 enzymethrough formation of a thioester bond intermediate. The E1-ublintermediate and an E2 associate, resulting in a thioester exchangewherein the ubl is transferred to the active site cysteine of the E2.The ubl is then conjugated to the target protein, either directly or inconjunction with an E3 ligase, through isopeptide bond formation withthe amino group of a lysine side chain in the target protein.

The biological consequence of ubl modification depends on the target inquestion. Ubiquitin is the best characterized of the ubls and aconsequence of modification by ubiquitination is the degradation ofpoly-ubiquitinated proteins by the 26S proteasome. Ubiquitin isconjugated to its target proteins through an enzymatic cascade involvingits specific E1 activating enzyme, Uba1 (ubiquitin activating enzyme,UAE), a conjugating enzyme from the family of E2s, and a ubiquitinligase from either the RING or HECT classes of E3s. See, Huang et al.,Oncogene. 23:1958-71 (2004). Target specificity is controlled by theparticular combination of E2 and E3 protein, with >40 E2s and >100 E3sbeing known at present. In addition to ubiquitin, there are at least 10ubiquitin-like proteins, each believed to be activated by a specific E1activating enzyme and processed through similar but distinct downstreamconjugation pathways. Other ubls for which E1 activating enzymes havebeen identified include Nedd8 (APPBP1-Uba3), ISG15 (UBE1L) and the SUMOfamily (Aos1-Uba2).

The ubl Nedd8 is activated by the heterodimer Nedd8-activating enzyme(APPBP1-Uba3) (NAE) and is transferred to a single E2 (Ubc12),ultimately resulting in ligation to cullin proteins. The function ofneddylation is the activation of cullin-based ubiquitin ligases involvedin the ubiquitination and hence turnover of many cell cycle and cellsignaling proteins, including p27 and I-κB. See Pan et al., Oncogene.23:1985-97, (2004). The ubl SUMO is activated by the heterodimer sumoactivating enzyme (Aos1-Uba2) (SAE) and is transferred to a single E2(Ubc9), followed by coordination with multiple E3 ligases, ultimatelyresulting in sumoylation of target proteins. Sumo modification canaffect the cellular localization of target proteins and proteinsmodified by SUMO family members are involved in nuclear transport,signal transduction and the stress response. See Seeler and Dejean, NatRev Mol Cell Biol. 4:690-9, (2003). The function of sumoylation includesactivation of cell signaling pathways (e.g., cytokine, WNT, growthfactor, and steroid hormone signaling) involved in transcriptionregulation; as well as pathways involved in control of genomic integrity(e.g., DNA replication, response to DNA damage, recombination andrepair). See Muller et al, Oncogene. 23:1998-2006, (2004). There areother ubls (e.g., ISG15, FAT10, Apg12p) for which the biologicalfunctions are still under investigation.

A particular pathway of importance which is regulated via E1 activatingenzyme activities is the ubiquitin-proteasome pathway (UPP). Asdiscussed above, the enzymes UAE and NAE regulate the UPP at twodifferent steps in the ubiquitination cascade. UAE activates ubiquitinin the first step of the cascade, while NAE, via activation of Nedd8, isresponsible for the activation of the cullin based ligases, which inturn are required for the final transfer of ubiquitin to certain targetproteins A functional UPP pathway is required for normal cellmaintenance. The UPP plays a central role in the turnover of many keyregulatory proteins involved in transcription, cell cycle progressionand apoptosis, all of which are important in disease states, includingtumor cells. See, e.g., King et al., Science 274: 1652-1659 (1996);Vorhees et al., Clin. Cancer Res., 9: 6316-6325 (2003); and Adams etal., Nat. Rev. Cancer, 4: 349-360 (2004). Proliferating cells areparticularly sensitive to inhibition of the UPP. See, Drexler, Proc.Natl. Acad. Sci., USA 94: 855-860 (1977). The role of the UPP pathway inoncogenesis has led to the investigation of proteasome inhibition as apotential anticancer therapy. For example, modulation of the UPP pathwayby inhibition of the 26S proteasome by VELCADE® (bortezomib) has provento be an effective treatment in certain cancers and is approved for thetreatment of relapsed and refractory multiple myeloma. Examples ofproteins whose levels are controlled by cullin-based ubiquitin ligaseswhich are downstream of NAE and UAE activity include the CDK inhibitorp27^(Kip1) and the inhibitor of NFκB, IκB. See, Podust et al., Proc.Natl. Acad. Sci., 97: 4579-4584, (2000), and Read et al., Mol. CellBiol., 20: 2326-2333, (2000). Inhibition of the degradation of p27 isexpected to block the progression of cells through the G1 and S phasesof the cell cycle. Interfering with the degradation of IκB shouldprevent the nuclear localization of NF-κB, transcription of variousNF-κB-dependent genes associated with the malignant phenotype, andresistance to standard cytotoxic therapies. Additionally, NF-κB plays akey role in the expression of a number of pro-inflammatory mediators,implicating a role for such inhibitors in inflammatory diseases.Furthermore, inhibition of UPP has been implicated as a useful targetfor additional therapeutics, such as inflammatory disorders, including,e.g., rheumatoid arthritis, asthma, multiple sclerosis, psoriasis andreperfusion injury; neurodegenerative disorders, including e.g.,Parkinson's disease, Alzheimer's disease, triplet repeat disorders;neuropathic pain; ischemic disorders, e.g., stroke, infarction, kidneydisorders; and cachexia. See, e.g., Elliott and Ross, Am J Clin Pathol.116:637-46 (2001); Elliott et al., J Mol Med. 81:235-45 (2003); Tarlacand Storey, J. Neurosci. Res. 74: 406-416 (2003); Mori et al.,Neuropath. Appl. Neurobiol., 31: 53-61 (2005); Manning, Curr PainHeadache Rep. 8: 192-8 (2004); Dawson and Dawson, Science 302: 819-822(2003); Kukan, J Physiol Pharmacol. 55: 3-15 (2004); Wojcik andDiNapoli, Stroke. 35:1506-18 (2004); Lazarus et al., Am J Physiol.27:E332-41 (1999).

Targeting E1 activating enzymes provides a unique opportunity tointerfere with a variety of biochemical pathways important formaintaining the integrity of cell division and cell signaling. E1activating enzymes function at the first step of ubl conjugationpathways; thus, inhibition of an E1 activating enzyme will specificallymodulate the downstream biological consequences of the ubl modification.As such, inhibition of these activating enzymes, and the resultantinhibition of downstream effects of ubl-conjugation, represents a methodof interfering with the integrity of cell division, cell signaling, andseveral aspects of cellular physiology which are important for diseasemechanisms. Thus, E1 enzymes such as UAE, NAE, and SAE, as regulators ofdiverse cellular functions, are potentially important therapeutictargets for the identification of novel approaches to treatment ofdiseases and disorders.

DESCRIPTION OF THE INVENTION

This invention provides compounds that are effective inhibitors of E1activating enzymes, particularly NAE. The compounds are useful forinhibiting E1 activity in vitro and in vivo, and are useful for thetreatment of disorders of cell proliferation, particularly cancers, andother disorders associated with E1 activity. Compounds of the inventionare of the general formula (I):

-   -    or a pharmaceutically acceptable salt thereof, wherein:    -   stereochemical configurations depicted at asterisked positions        indicate relative stereochemistry;    -   Ring A is selected from the group consisting of:

-   -    wherein one ring nitrogen atom in Ring A optionally is        oxidized;    -   X is —C(R^(f1))₂, —N(R^(f2))—, or —O—;    -   Y is —O—, —S—, or —C(R^(m))(R^(n))—;    -   R^(a) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(b) together form ═O; or        R^(a) and R^(c) together form a bond;    -   R^(b) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; or R^(b) and R^(a)        together form ═O; or R^(b), taken together with R^(d) and the        intervening carbon atoms, forms a fused cyclopropane ring, which        is optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or R^(b),        taken together with R^(e) and the intervening carbon atoms,        forms a fused cyclopropane ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic;    -   R^(c) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or R^(c) and R^(a) together form a bond;        or R^(c) and R^(d) together form ═O;    -   R^(d) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; or R^(d) and R^(c)        together form ═O; or R^(d), taken together with R^(b) and the        intervening carbon atoms, forms a fused cyclopropane ring, which        is optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or R^(d),        taken together with R^(e′) and the intervening carbon atoms,        forms a fused cyclopropane ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic;    -   R^(e) is hydrogen, or C₁₋₄ aliphatic; or R^(e), taken together        with one R^(f) and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic; or R^(e), taken together with R^(m) and the        intervening carbon atoms, forms a fused cyclopropane ring, which        is optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or R^(e),        taken together with R^(b) and the intervening carbon atoms,        forms a fused cyclopropane ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic; or R^(e′), taken together        with R^(m) and the intervening carbon atoms, forms a fused        cyclopropane ring, which is optionally substituted with one or        two substituents independently selected from fluoro or C₁₋₄        aliphatic; or R^(e′), taken together with R^(d) and the        intervening carbon atoms, forms a fused cyclopropane ring, which        is optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic, or        C₁₋₄ fluoroaliphatic, provided that if X is —O— or —NH—, then        R^(f) is not fluoro; or two R^(f) taken together form ═O; or two        R^(f), taken together with the carbon atom to which they are        attached, form a 3- to 6-membered carbocyclic ring; or one        R^(f), taken together with R^(e) and the intervening carbon        atoms, forms a 3- to 6-membered spirocyclic ring, which is        optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or one        R^(f), taken together with an adjacent R^(f1) and the        intervening carbon atoms, forms a cyclopropyl ring, which is        optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or one        R^(f) and one R^(f1) together form a double bond;    -   each R^(1f) is independently hydrogen or fluoro; or one R^(f1),        taken together with an adjacent R^(f) and the intervening carbon        atoms forms a cyclopropyl ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic; or one R^(f1) and one R^(f) together form a        double bond;    -   R^(f2) is hydrogen, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(g) is hydrogen, halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,        —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O) R⁵,        —NR⁴C(O) N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶,        —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶,        —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,        —C(O) N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵,        —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵,        —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl;    -   each R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂,        —SR⁶, or an optionally substituted C₁₋₄ aliphatic group;    -   R^(j) is hydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted aliphatic, aryl, or heteroaryl group;    -   R^(k) is hydrogen, halo, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted C₁₋₄ aliphatic group;    -   R^(m) is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted        C₁₋₄ aliphatic group; or R^(m) and R^(n) together form ═O or        ═C(R⁵)₂; or R^(m) and R^(e), taken together with the intervening        carbon atoms, form a fused cyclopropane ring, which is        optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or R^(m)        and R^(e′), taken together with the intervening carbon atoms,        form a fused cyclopropane ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic;    -   R^(n) is hydrogen, fluoro, or an optionally substituted C₁₋₄        aliphatic group; or R^(m) and R^(n) together form ═O or ═C(R⁵)₂;    -   each R⁴ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on        the same nitrogen atom, taken together with the nitrogen atom,        form an optionally substituted 4- to 8-membered heterocyclyl        ring having, in addition to the nitrogen atom, 0-2 ring        heteroatoms independently selected from N, O, and S;    -   R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted;    -   R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted, or an optionally substituted 5- or 6-membered aryl,        heteroaryl, or heterocyclyl ring; or    -   R^(4x) and R^(4y), taken together with the nitrogen atom to        which they are attached, form an optionally substituted 4- to        8-membered heterocyclyl ring having, in addition to the nitrogen        atom, 0-2 ring heteroatoms independently selected from N, O, and        S; and    -   each R⁵ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀        ar(C₁₋₄)alkyl;    -   each R⁶ independently is an optionally substituted aliphatic,        aryl, or heteroaryl group; and    -   m is 0, 1, 2, or 3, provided that Y is —C(R^(m))(R^(n))— when m        is 0.

In some embodiments, the invention relates to a compound of formula (I),characterized by formula (I-A):

-   -    or a pharmaceutically acceptable salt thereof, wherein:    -   stereochemical configurations depicted at asterisked positions        indicate relative stereochemistry;    -   Ring A is selected from the group consisting of:

-   -    wherein one ring nitrogen atom in Ring A optionally is        oxidized;    -   X is —CH₂—, —CHF—, —CF₂—, —NH—, or —O—;    -   Y is —O—, —S—, or —C(R^(m))(R^(n))—;    -   R^(a) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, C₁₋₄ fluoroaliphatic,        or a C₁₋₄ aliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y));    -   R^(b) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(c) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC (O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, C₁₋₄ fluoroaliphatic,        or a C₁₋₄ aliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y));    -   R^(d) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(e) is hydrogen, or C₁₋₄ aliphatic; or R^(e), taken together        with one R^(f) and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic, or        C₁₋₄ fluoroaliphatic, provided that if X is —O— or —NH—, then        R^(f) is not fluoro; or two R^(f) taken together form ═O; or two        R^(f), taken together with the carbon atom to which they are        attached, form a 3- to 6-membered carbocyclic ring; or one        R^(f), taken together with R^(e) and the intervening carbon        atoms, forms a 3- to 6-membered spirocyclic ring;    -   R^(g) is hydrogen, halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,        —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,        —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶,        —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶,        —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,        —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵,        —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵,        —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl;    -   each R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂,        —SR⁶, or an optionally substituted C₁₋₄ aliphatic group;    -   R^(j) is hydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted aliphatic, aryl, or heteroaryl group;    -   R^(k) is hydrogen, halo, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted C₁₋₄ aliphatic group;    -   R^(m) is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted        C₁₋₄ aliphatic group; and    -   R^(n) is hydrogen, fluoro, or an optionally substituted C₁₋₄        aliphatic group; or    -   R^(m) and R^(n) together form ═O or ═C(R⁵)₂;    -   each R⁴ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on        the same nitrogen atom, taken together with the nitrogen atom,        form an optionally substituted 4- to 8-membered heterocyclyl        ring having, in addition to the nitrogen atom, 0-2 ring        heteroatoms independently selected from N, O, and S;    -   R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted;    -   R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted, or an optionally substituted 5- or 6-membered aryl,        heteroaryl, or heterocyclyl ring; or    -   R^(4x) and R^(4y), taken together with the nitrogen atom to        which they are attached, form an optionally substituted 4- to        8-membered heterocyclyl ring having, in addition to the nitrogen        atom, 0-2 ring heteroatoms independently selected from N, O, and        S; and each R⁵ independently is hydrogen or an optionally        substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀        ar(C₁₋₄)alkyl;    -   each R⁶ independently is an optionally substituted aliphatic,        aryl, or heteroaryl group; and    -   m is 1, 2, or 3.

Compounds of the invention include those described generally above, andare further defined and illustrated by the detailed description andexamples herein.

As used herein, the term “E1,” “E1 enzyme,” or “E1 activating enzyme”refers to any one of a family of related ATP-dependent activatingenzymes involved in activating or promoting ubiquitin or ubiquitin-like(collectively “ubl”) conjugation to target molecules. E1 activatingenzymes function through an adenylation/thioester intermediate formationto transfer the appropriate ubl to the respective E2 conjugating enzymethrough a transthiolation reaction. The resulting activated ubl-E2promotes ultimate conjugation of the ubl to a target protein. A varietyof cellular proteins that play a role in cell signaling, cell cycle, andprotein turnover are substrates for ubl conjugation which is regulatedthrough E1 activating enzymes (e.g., NAE, UAE, SAE). Unless otherwiseindicated by context, the term “E1 enzyme” is meant to refer to any E1activating enzyme protein, including, without limitation, nedd8activating enzyme (NAE (APPBP1/Uba3)), ubiquitin activating enzyme (UAE(Uba1)), sumo activating enzyme (SAE (Aos1/Uba2)), or ISG15 activatingenzyme (Ube1L), preferably human NAE, SAE or UAE, and more preferablyNAE.

The term “E1 enzyme inhibitor” or “inhibitor of E1 enzyme” is used tosignify a compound having a structure as defined herein, which iscapable of interacting with an E1 enzyme and inhibiting its enzymaticactivity. Inhibiting E1 enzymatic activity means reducing the ability ofan E1 enzyme to activate ubiquitin like (ubl) conjugation to a substratepeptide or protein (e.g., ubiquitination, neddylation, sumoylation). Invarious embodiments, such reduction of E1 enzyme activity is at leastabout 50%, at least about 75%, at least about 90%, at least about 95%,or at least about 99%. In various embodiments, the concentration of E1enzyme inhibitor required to reduce an E1 enzymatic activity is lessthan about 1 μM, less than about 500 nM, less than about 100 nM, lessthan about 50 nM, or less than about 10 nM.

In some embodiments, such inhibition is selective, i.e., the E1 enzymeinhibitor reduces the ability of one or more E1 enzymes (e.g., NAE, UAE,or SAE) to promote ubl conjugation to substrate peptide or protein at aconcentration that is lower than the concentration of the inhibitor thatis required to produce another, unrelated biological effect. In somesuch embodiments, the E1 enzyme inhibitor reduces the activity of one E1enzyme at a concentration that is lower than the concentration of theinhibitor that is required to reduce enzymatic activity of a differentE1 enzyme. In other embodiments, the E1 enzyme inhibitor also reducesthe enzymatic activity of another E1 enzyme, preferably one that isimplicated in regulation of pathways involved in cancer (e.g., NAE andUAE).

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

The term “aliphatic”, as used herein, means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation, but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof, such as cycloalkyl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In various embodiments, thealiphatic group has one to ten, one to eight, one to six, one to four,or one, two, or three carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from one to twelve carbon atoms. For purposes of the presentinvention, the term “alkyl” will be used when the carbon atom attachingthe aliphatic group to the rest of the molecule is a saturated carbonatom. However, an alkyl group may include unsaturation at other carbonatoms. Thus, alkyl groups include, without limitation, methyl, ethyl,propyl, allyl, propargyl, butyl, pentyl, and hexyl. The term “alkoxy”refers to an —O-alkyl radical.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on a cycloaliphatic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, C₁, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on an arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Thus, when used in reference to a ring atom of a heteroaryl,the term “nitrogen” includes an oxidized nitrogen (as in pyridineN-oxide). Certain nitrogen atoms of 5-membered heteroaryl groups alsoare substitutable, as further defined below. Heteroaryl groups include,without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

In some embodiments, two adjacent substituents on a heteroaryl ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring”, or “heteroaryl group”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “aromatic ring” and “aromatic ring system”refer to an optionally substituted mono-, bi-, or tricyclic group having0-6, preferably 0-4 ring heteroatoms, and having 6, 10, or 14 πelectrons shared in a cyclic array. Thus, the terms “aromatic ring” and“aromatic ring system” encompass both aryl and heteroaryl groups.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain which is optionallysubstituted.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from one to six, from one to four, from oneto three, from one to two, or from two to three. A substituted alkylenechain is a polymethylene group in which one or more methylene hydrogenatoms is replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group. An alkylenechain also may be substituted at one or more positions with an aliphaticgroup or a substituted aliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R*)═C(R*)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R*)—, —N(R⁺)CO—,—N(R+)C(O)N(R⁺)—, —N(R⁺)CO₂—, —C(O)N(R⁺)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —O C(O)N(R⁺)—, —C(NR⁺)═N, —C(OR*)═N—, —N(R⁺)—N(R⁺)—,or —N(R⁺)S(O)₂—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a five to eight membered aromatic or non-aromatic ring having, inaddition to the nitrogen atom, zero to two ring heteroatoms selectedfrom N, O, and S. Each R* independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include —CH₂OCH₂—, —CH₂O(CH₂)₂—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—,—(CH₂)₂OCH₂—, —(CH₂)₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—, —(CH₂)₃O(CH₂)—,—(CH₂)₃O(CH₂)₂—, and —(CH₂)₄O(CH₂)—. Other examples of alkylene chainsthat are “interrupted” with functional groups include —CH₂GCH₂—,—CH₂G(CH₂)₂—, —CH₂G(CH₂)₃—, —CH₂G(CH₂)₄—, —(CH₂)₂GCH₂—, —(CH₂)₂G(CH₂)₂—,—(CH₂)₂G(CH₂)₃—, —(CH₂)₃G(CH₂)—, —(CH₂)₃G(CH₂)₂—, and —(CH₂)₄G(CH₂)—,wherein G is one of the “interrupting” functional groups listed above.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above and thevariables V¹, V², T¹, T², T³, and T⁴, are intended to be read from leftto right, with a corresponding left-to-right reading of the formula orstructure in which the variable appears.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention. A stable or chemically feasible compound is one inwhich the chemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., preferably from about−20° C. to about +40° C., in the absence of moisture or other chemicallyreactive conditions, for at least a week, or a compound which maintainsits integrity long enough to be useful for therapeutic or prophylacticadministration to a patient.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The term “substitutable”, when used inreference to a designated atom, means that attached to the atom is ahydrogen radical, which can be replaced with the radical of a suitablesubstituent.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and thesubstituents may be either the same or different. As used herein, theterm “independently selected” means that the same or different valuesmay be selected for multiple instances of a given variable in a singlecompound.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂, —NR⁺CO₂R^(o),—O—CO₂R^(o), —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*, —C(O)R*,—C(O)N(R⁺)₂, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*, —N(R⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)₂, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —P(O)(R*)₂,—P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) is anoptionally substituted aliphatic or aryl group, and R⁺ and R* are asdefined above, or two adjacent substituents, taken together with theirintervening atoms, form a 5- to 6-membered unsaturated or partiallyunsaturated ring having 0-3 ring atoms selected from the groupconsisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R⁺)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where each R* and R^(o) is asdefined above. For the purposes of clarity, the term “substitutedaliphatic” refers to an aliphatic group having at least onenon-aliphatic substituent.

Suitable substituents on a substitutable nitrogen atom of a heteroarylor heterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R^(o),—C(O)—C(O)R*—C(O)CH₂C(O)R*, —SO₂R^(o), —SO₂N(R*)₂, —C(═S)N(R*)₂,—C(═NH)—N(R*)₂, and —NR*SO₂R^(o); wherein each R* and R^(o) is asdefined above.

Unless otherwise stated, structures depicted herein are meant to includecompounds which differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structureexcept for the replacement of a hydrogen atom by a deuterium or tritium,or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon arewithin the scope of the invention.

It also will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention. Unless stereochemical configuration is expressly defined,structures depicted herein are meant to include all stereochemical formsof the structure; i.e., the R and S configurations for each asymmetriccenter. Therefore, unless otherwise indicated, single stereochemicalisomers as well as enantiomeric and diastereomeric mixtures of thepresent compounds are within the scope of the invention. By way ofexample, the compounds of formula (I) wherein R^(a) is hydroxy can haveR or S configuration at the carbon atom bearing R^(a). Both the R andthe S stereochemical isomers, as well as all mixtures thereof, areincluded within the scope of the invention.

Where stereochemical configuration at a given asymmetric center isdefined by structure, unless stated otherwise, the depictedconfiguration indicates stereochemistry relative to other asymmetriccenters in the molecule. Where stereochemical configuration is definedby chemical name, the designations (rel), (R*), and (S*) indicaterelative stereochemistry, while the designations (R), (S), (+), (−), and(abs) indicate absolute stereochemistry.

In the compounds of formula (I), stereochemical configurations depictedat asterisked positions indicate relative stereochemistry, unlessexpressly stated to indicate absolute stereochemistry. Preferably, thediastereomeric purity of the compound is at least 80%, more preferablyat least 90%, still more preferably at least 95%, and most preferably atleast 99%. As used herein, the term “diastereomeric purity” refers tothe amount of a compound having the depicted relative stereochemistry,expressed as a percentage of the total amount of all diastereomerspresent.

In some embodiments, stereochemical configurations depicted atasterisked positions indicate absolute as well as relativestereochemistry. Preferably, the enantiomeric purity of the compound isat least 80%, more preferably at least 90%, still more preferably atleast 95%, and most preferably at least 99%. As used herein, the term“enantiomeric purity” refers to the amount of a compound having thedepicted absolute stereochemistry, expressed as a percentage of thetotal amount of the depicted compound and its enantiomer.

Methods for determining diastereomeric and enantiomeric purity arewell-known in the art. Diastereomeric purity can be determined by anyanalytical method capable of quantitatively distinguishing between acompound and its diastereomers. Examples of suitable analytical methodsinclude, without limitation, nuclear magnetic resonance spectroscopy(NMR), gas chromatography (GC), and high performance liquidchromatography (HPLC). Similarly, enantiomeric purity can be determinedby any analytical method capable of quantitatively distinguishingbetween a compound and its enantiomer. Examples of suitable analyticalmethods include, without limitation, GC or HPLC, using a chiral columnpacking material. Enantiomers may also be distinguishable by NMR iffirst derivatized with an optically enriched derivatizing agent, e.g.,Mosher's acid.

In the compounds of formula (I), X is —C(R^(f1))₂, —N(R^(f2))—, or —O—.Each R^(f1) is independently hydrogen or fluoro; or one R^(f1), takentogether with an adjacent R^(f) and the intervening carbon atoms forms acyclopropyl ring; or one R^(f1) and one R^(f) together form a doublebond. R^(f2) is hydrogen, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic. Insome embodiments, X is —CH₂—, —CHF—, —CF₂—, —NH—, or —O—. In certainembodiments, X is —CH₂—, —NH—, or —O—. In certain particularembodiments, X is —O—.

In the compounds of formula (I), Y is —O—, —S—, or —C(R^(m))(R^(n))—,where R^(m) and R^(n) are as described above. In some embodiments, R^(m)is hydrogen, fluoro, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, orC₁₋₄ aliphatic, or R^(m) and R^(n) together form ═O. In someembodiments, Y is —O— or —CH₂.

In the compounds of formula (I), m is 0, 1, 2, or 3, provided that Y is—C(R^(m))(R^(n))— when m is 0. In some embodiments, m is 1, 2, or 3. Incertain particular embodiments, m is 1.

In the compounds of formula (I), R^(a) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶,—NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or aC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with oneor two substituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); orR^(a) and R^(b) together form ═O; or R^(a) and R^(c) together form abond. In some embodiments R^(a) is selected from the group consisting ofhydrogen, fluoro, —CN, N₃, C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic,—OR^(5x), —NH(R⁴), —N(H)CO₂R⁵, —N(H)C(O)R⁵, —C(O)NHR⁴, —C(O)R⁵,—OC(O)NHR⁴, —OC(O)R⁵, and —OC(O)OR⁵. In some embodiments, R^(a) isselected from the group consisting of hydrogen, —OH, —OCH₃, C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, and fluoro. In certain embodiments,R^(a) is selected from the group consisting of hydrogen, —OH, —OCH₃,—CH₃, and fluoro. In certain particular embodiments, R^(a) is —OH.

In the compounds of formula (I), R^(c) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶,—NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or aC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with oneor two substituents independently selected from the group consisting of—OR⁵, —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); orR^(c) and R^(a) together form a bond; or R^(c) and R^(d) together from═O. In some embodiments, R^(c) is hydrogen, fluoro, —CN, N₃, C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, —OR^(5x), —NH(R⁴), —N(H)CO₂R⁵,—N(H)C(O)R⁵, —C(O)NHR⁴, —C(O)R⁵, —OC(O)NHR⁴, —OC(O)R⁵, and —OC(O)OR⁵. Incertain embodiments, R^(c) is hydrogen, —OH, —OCH₃, or fluoro. Incertain particular embodiments, R^(c) is hydrogen or —OH.

In the compounds of formula (I), R^(b) is selected from the groupconsisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; or R^(b) and R^(a) together form ═O; or R^(b), takentogether with R^(d) and the intervening carbon atoms, forms a fusedcyclopropane ring, which is optionally substituted with one or twosubstituents independently selected from fluoro or C₁₋₄ aliphatic; orR^(b), taken together with R^(e) and the intervening carbon atoms, formsa fused cyclopropane ring, which is optionally substituted with one ortwo substituents independently selected from fluoro or C₁₋₄ aliphatic.

In the compounds of formula (I), R^(d) is selected from the groupconsisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; or R^(d) and R^(c) together form ═O; or R^(d), takentogether with R^(b) and the intervening carbon atoms, forms a fusedcyclopropane ring, which is optionally substituted with one or twosubstituents independently selected from fluoro or C₁₋₄ aliphatic; orR^(d), taken together with R^(e′) and the intervening carbon atoms,forms a fused cyclopropane ring, which is optionally substituted withone or two substituents independently selected from fluoro or C₁₋₄aliphatic.

In some embodiments, each of R^(b) and R^(d) independently is selectedfrom the group consisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic. In some embodiments, one of R^(b) and R^(d) is C₁₋₄aliphatic and the other is hydrogen. In some embodiments, R^(b) andR^(d) are each hydrogen.

In one embodiment, R^(a) and R^(c) are each —OH, and R^(b) and R^(d) areeach hydrogen. In another embodiment, R^(a) is —OH, and each of R^(b),R^(c), and R^(d) is hydrogen. In another embodiment, R^(a) is —OH, R^(c)is fluoro or —OCH₃, and R^(b) and R^(d) are each hydrogen. In anotherembodiment, R^(a) is —OH, R^(b) is —CH₃, R^(c) is hydrogen or —OH, andR^(d) is hydrogen. In another embodiment, R^(a) and R^(c) together forma bond, and R^(b) and R^(d) are each hydrogen.

In the compounds of formula (I), each R^(f) independently isindependently hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic,provided that if X is —O— or —NH—, then R^(f) is not fluoro; or twoR^(f) taken together form ═O; or two R^(f), taken together with thecarbon atom to which they are attached, form a 3- to 6-memberedcarbocyclic ring; or one R^(f), taken together with R^(e) and theintervening carbon atoms, forms a 3- to 6-membered spirocyclic ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; or one R^(f),taken together with an adjacent R^(f1) and the intervening carbon atomsforms a cyclopropyl ring, which is optionally substituted with one ortwo substituents independently selected from fluoro or C₁₋₄ aliphatic;or one R^(f) and one R^(f1) together form a double bond. In someembodiments, each R^(f) independently is hydrogen or C₁₋₄ aliphatic. Insome such embodiments, each R^(f) independently is hydrogen or —CH₃. Incertain embodiments, one R^(f) is hydrogen or —CH₃, and the other R^(f)is hydrogen. In certain particular embodiments, each R^(f) is hydrogen.

In the compounds of formula (I), R^(e) is hydrogen, or C₁₋₄ aliphatic;or R^(e), taken together with one R^(f) and the intervening carbonatoms, forms a 3- to 6-membered spirocyclic ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic; or R^(e), taken together with R^(m) and theintervening carbon atoms, forms a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; or R^(e), taken together withR^(b) and the intervening carbon atoms, forms a fused cyclopropane ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic. In someembodiments, R^(e) is hydrogen or C₁₋₄ aliphatic. In some suchembodiments, R^(e) is hydrogen or —CH₃. In certain embodiments, R^(e) ishydrogen.

In the compounds of formula (I), R^(e′) is hydrogen or C₁₋₄ aliphatic;or R^(e′), taken together with R^(m) and the intervening carbon atoms,forms a fused cyclopropane ring, which is optionally substituted withone or two substituents independently selected from fluoro or C₁₋₄aliphatic; or R^(e′), taken together with R^(d) and the interveningcarbon atoms, forms a fused cyclopropane ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic. In some embodiments, R^(e′) is hydrogen orC₁₋₄ aliphatic. In certain particular embodiments, R^(e′) is hydrogen.

In the compounds of formula (I), Ring A is selected from the groupconsisting of:

where R^(g), R^(h), R^(j) and R^(k) are as defined above and as furtherdefined below.

In the compounds of formula (I), each R^(h) independently is hydrogen,halo, —CN—, —OR⁵, —N(R⁴)₂, —SR⁶, or an optionally substituted C₁₋₄aliphatic group. In some embodiments, each R^(h) independently ishydrogen, halo, —CN, —OH, —O—(C₁₋₄ aliphatic), —NH₂, —NH—(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —SH, —S—(C₁₋₄ aliphatic), or anoptionally substituted C₁₋₄ aliphatic group. In certain embodiments,R^(h) is hydrogen or chloro. In certain particular embodiments, R^(h) ishydrogen.

In the compounds of formula (I), each R^(j) independently is hydrogen,—OR⁵, —N(R⁴)₂, —SR⁶, or an optionally substituted aliphatic, aryl, orheteroaryl group. In some embodiments, each R^(j) independently ishydrogen, —OH, —O—(C₁₋₄ aliphatic), —NH₂, —NH—(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —SH, —S—(C₁₋₄ aliphatic), or an optionally substituted C₁₋₄aliphatic group. In certain embodiments, R^(j) is hydrogen or C₁₋₄aliphatic. In certain particular embodiments, R^(h) is hydrogen.

In the compounds of formula (I), R^(k) is hydrogen, halo, —OR⁵, —N(R⁴)₂,—SR⁶, or an optionally substituted C₁₋₄ aliphatic group. In someembodiments, each R^(k) independently is hydrogen, halo, —OH, —O—(C₁₋₄aliphatic), —NH₂, —NH—(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —SH,—S—(C₁₋₄ aliphatic), or an optionally substituted C₁₋₄ aliphatic group.In certain embodiments, R^(k) is hydrogen, halo, or C₁₋₄ aliphatic. Incertain particular embodiments, R^(k) is hydrogen.

In some embodiments, the compound of formula (I) is characterized by atleast one of the following features:

-   -   (a) X is —O—;    -   (b) Y is —O— or —CH₂—;    -   (c) R^(a) is —OH;    -   (d) R^(b) and R^(d) are each independently hydrogen or C₁₋₄        aliphatic;    -   (e) R^(c) is hydrogen, fluoro, or —OR⁵;    -   (f) R^(e) and R^(e′) are each hydrogen;    -   (g) each R^(f) is hydrogen;    -   (h) each R^(h) is hydrogen;    -   (i) R^(j) is hydrogen or C₁₋₄ aliphatic;    -   (j) R^(k) is hydrogen, halo, or C₁₋₄ aliphatic;    -   (k) m is 1; and    -   (l) stereochemical configurations depicted at asterisked        positions indicate absolute stereochemistry.

In the compounds of formula (I), R^(g) is hydrogen, halo, —NO₂, —CN,—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O) N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵,—C(R⁶)═N—OR⁵, or an optionally substituted aliphatic, aryl, heteroaryl,or heterocyclyl.

In some embodiments, R^(g) is hydrogen, C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(1g), —R^(2g), -T¹-R^(1g), -T¹-R^(2g),-V¹-T¹-R^(1g), and -V¹-T¹-R^(2g), where the variables R^(1g), R^(2g),V¹, and T¹ have the values described below.

T¹ is a C₁₋₆ alkylene chain substituted with 0-2 independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)—C(═NR⁴)—,—N(R⁴)CO₂—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —OC(O)—, —OC(O)N(R⁴)—, —C(O)—,—CO₂—, —C(O)N(R⁴)—, —C(═NR⁴)—N(R⁴)—, —C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or—C(R⁶)═N—O—, and wherein T¹ or a portion thereof optionally forms partof a 3-7 membered ring.

In some embodiments, T¹ is a C₁₋₄ alkylene chain optionally substitutedwith one or two groups independently selected from fluoro or a C₁₋₄aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with one or twosubstituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)).

In certain embodiments, T¹ is a C₁₋₄ alkylene chain optionallysubstituted with one or two groups independently selected from fluoro,C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic.

Each R^(3a) independently is selected from the group consisting of —F,—OH, —O(C₁₋₄ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄ alkyl), —CO₂H, —CO₂(C₁₋₄alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₄ alkyl).

Each R^(3b) independently is a C₁₋₃ aliphatic optionally substitutedwith R^(3a) or R⁷, or two substituents R^(3b) on the same carbon atom,taken together with the carbon atom to which they are attached, form a3- to 6-membered cycloaliphatic ring.

Each R⁷ independently is an optionally substituted aryl or heteroarylring.

V¹ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—,—N(R⁴)C(═NR⁴)—, —N(R⁴)CO₂—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —OC(O)—,—OC(O)N(R⁴)—, —C(O)—, —CO₂—, —C(O)N(R⁴)—, —C(O)N(R⁴)—O—,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)—, —C(═NR⁴)—N(R⁴)—,—C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or —C(R⁶)═N—O—. In some embodiments, V¹ is—N(R⁴)C(O)—, —N(R⁴)C(O)N(R⁴)—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, or—N(R⁴)CO₂—. In certain such embodiments, V¹ is —N(R⁴)C(O)— or—N(R⁴)C(O)N(R⁴)—. In other embodiments, V¹ is —C(R⁵)═C(R⁵), —C≡C—, —O—,—S—, or —N(R⁴)—.

Each R^(1g) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring.

Each R^(2g) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O) R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O) N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O) R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.

The invention also relates to a subgenus of the compounds of formula(I), characterized by formula (II):

or a pharmaceutically acceptable salt thereof, wherein Ring A and thevariables X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), and mhave the values and preferred values described above for formula (I).

The invention also relates to a subgenus of the compounds of formula(I), characterized by formula (III):

or a pharmaceutically acceptable salt thereof, wherein Q is ═N— or═C(R^(k))—, and the variables X, Y, R^(a), R^(b), R^(c), R^(d), R^(e),R, R^(g), R^(h), R^(j), R^(k), and m have the values and preferredvalues described above for formula (I).

Various particular embodiments of the invention relate to subgenera ofthe compounds of formula (III), represented by formulae (III-A),(III-B), (III-C), (III-D), (III-E), and (III-F):

or a pharmaceutically acceptable salt thereof, wherein the variables Q,R^(a), R^(c), R^(g), R^(h) and R^(j) have the values and preferredvalues described herein for formula (I).

One embodiment of the invention relates to a compound of formula (I),wherein R^(g) is an optionally substituted aryl, heteroaryl, orheterocyclyl group. In some such embodiments, the invention relates to asubgenus of the compounds of formula (I), characterized by formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is an optionally substituted 5- or 6-membered aryl or heteroarylring having zero to three ring nitrogen atoms and optionally oneadditional ring heteroatom selected from oxygen and sulfur; and

the variables Q, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(h),R^(j), and m have the values and preferred values described above forformula (I).

In some embodiments, R^(g) is an optionally substituted furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, wherein onering nitrogen atom in R^(g) optionally is oxidized. In certainparticular embodiments, R^(g) is an optionally substituted phenyl,imidazolyl, or triazolyl.

Substitutable ring carbon atoms in Ring B preferably are substitutedwith 0-3 substituents independently selected from the group consistingof halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionallysubstituted aliphatic, or an optionally substituted aryl, heterocyclyl,or heteroaryl group; or two adjacent substituents, taken together withthe intervening ring atoms, form an optionally substituted fused 4- to8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S.

In some embodiments, Ring B is substituted with 0-2 substituentsindependently selected from the group consisting of halo, —CN, —N(R⁴)₂,—NR⁴C(O)R⁵, —NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, —OR⁵, or aC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)). Thevariables R⁴, R⁵, R⁶, R^(4x), R^(4y), and R^(5x) have the valuesdescribed above for formula (I).

Another embodiment of the invention relates to a compound of formula(I), wherein R^(g) is -V¹-T¹-R^(1g), —V¹-R^(1g), -T¹-R^(1g), or-T¹-V¹-R^(1g). R^(1g) is an optionally substituted mono- or bicyclicaryl, heteroaryl, heterocyclyl, or cycloaliphatic group. In someembodiments, C₁₋₄ alkylene chain optionally substituted with one or twogroups independently selected from fluoro or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)). In certainembodiments, T¹ is a C₁₋₄ alkylene chain optionally substituted with oneor two groups independently selected from fluoro, C₁₋₄ aliphatic, andC₁₋₄ fluoroaliphatic. In some embodiments, V¹ is —N(R⁴)C(O)—,—N(R⁴)C(O)N(R⁴)—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, or —N(R⁴)CO₂—. In certainsuch embodiments, V¹ is —N(R⁴)C(O)— or —N(R⁴)C(O)N(R⁴)—. In otherembodiments, V¹ is —C(R⁵)═C(R⁵), —C≡C—, —O—, —S—, or —N(R⁴)—. In certainsuch embodiments, V¹ is —N(R⁴)—.

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   V¹ is —N(R⁸)—, —O—, or —S—;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   T¹ is a C₁₋₄ alkylene chain optionally substituted with one or        two groups independently selected from fluoro or a C₁₋₄        aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with        one or two substituents independently selected from the group        consisting of —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and        —C(O)N(R^(4x))(R^(4y));    -   Ring C is an optionally substituted 3- to 8-membered        heterocyclyl or cycloaliphatic ring, or an optionally        substituted 5- or 6-membered aryl or heteroaryl ring; and    -   the variables Q, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),        R^(h), R^(j), and m have the values and preferred values        described above for formula (I).

In some such embodiments, T¹ is a C₁₋₄ alkylene chain optionallysubstituted with one or two groups independently selected from fluoro,C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic.

In some embodiments, Ring C is substituted with 0-2 R^(o) and 0-2R^(8o), where:

-   -   each R^(o) independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,        —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂,        —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,        —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,        —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂,        —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,        —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,        —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substituted        aliphatic, or an optionally substituted aryl, heterocyclyl, or        heteroaryl group; or two R^(o) on the same saturated ring carbon        atom, taken together with the carbon atom, form an optionally        substituted 3- to 8-membered spirocyclic cycloaliphatic or        heterocyclyl ring; or two adjacent R^(o), taken together with        the intervening ring atoms, form an optionally substituted fused        4- to 8-membered aromatic or non-aromatic ring having 0-3 ring        heteroatoms selected from the group consisting of O, N, and S;    -   each R^(8o) independently is selected from the group consisting        of C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, halo, —OR^(5x),        —N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic        optionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)),        —CO₂R^(5x), or —C(O)N(R^(4x))(R⁴); and    -   the variables R^(4x), R^(4y), and R^(5x) have the values        described above for formula (I).

In some such embodiments, Ring C is a C₃₋₆ cycloaliphatic, phenyl,pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolinyl,imidazolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, or tetrahydropyrimidinyl ring, any of which issubstituted with 0-2 R^(o) and 0-2 R^(8o).

In certain embodiments, T¹ is a C₁₋₂ alkylene chain optionallysubstituted with one or two groups independently selected from fluoro ora C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with oneor two substituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R⁴), andRing C is a C₃₋₆ cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring,any of which is substituted with 0-2 R^(8o) and optionally is fused toan optionally substituted benzene, dioxolane, or dioxane ring.

Another embodiment of the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   T¹ is a C₁₋₄ alkylene chain optionally substituted with one or        two groups independently selected from fluoro or a C₁₋₄        aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with        one or two substituents independently selected from the group        consisting of —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and        —C(O)N(R^(4x))(R^(4y));    -   Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic        ring, or a 5- or 6-membered aryl or heteroaryl ring, any of        which rings is substituted with 0-2 R^(o) and 0-2 R^(8o); and    -   the variables Q, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),        R^(h), R^(j), R^(o), R^(8o), R^(4x), R^(4y), R^(5x), and m have        the values and preferred values described above for formulae        (I)-(V).

In a particular embodiment, the invention relates to a compound offormula (VI) or a pharmaceutically acceptable salt thereof, wherein:

-   -   T¹ is a C₁₋₂ alkylene chain optionally substituted with one or        two groups independently selected from fluoro or a C₁₋₄        aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with        one or two substituents independently selected from the group        consisting of —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and        —C(O)N(R^(4x))(R^(4y)); and    -   Ring C is phenyl, which is substituted with 0-2 R^(8o) and        optionally is fused to an optionally substituted benzene,        dioxolane, or dioxane ring.

Another embodiment of the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   V² is —N(R⁸)—, —O—, or —S—;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   Ring D is an optionally substituted aryl, heteroaryl,        heterocyclyl, or cycloaliphatic ring; and    -   the variables Q, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),        R^(h), R^(j), and m have the values and preferred values        described above for formula (I).

In some embodiments, V² is —N(R⁸)—. In certain embodiments, V² is —NH—.

In some embodiments, Ring D is a mono-, bi-, or tricyclic ring system.In some embodiments, Ring D is a mono- or bicyclic ring system. In somesuch embodiments, Ring D selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,bicycloheptanyl and bicyclooctanyl. In certain embodiments, Ring D is anoptionally substituted indanyl, tetrahydronaphthyl, or chromanyl.

Ring D may be unsubstituted or may be substituted on either or both ofits component rings, and the substituents may be the same or different.In particular, each substitutable saturated ring carbon atom in Ring Dis unsubstituted or substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵,═N—NHC(O)R⁵, ═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(p). Each substitutableunsaturated ring carbon atom in Ring D is unsubstituted or substitutedwith —R^(p). Each substitutable ring nitrogen atom in Ring D isunsubstituted or substituted with —R^(9p). The variables R^(p) andR^(9p) have the values described below.

Each R^(p) independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵,—CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O) R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substitutedaliphatic, or an optionally substituted aryl, heterocyclyl, orheteroaryl group; or two R^(p) on the same saturated carbon atom, takentogether with the carbon atom to which they are attached, form anoptionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring.

Each R^(9p) independently is —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionally substituted with R³ or R⁷.

In some embodiments, each R^(p) independently is selected from the groupconsisting of halo, C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, —R^(1p),—R^(2p), -T²-R^(1p), and -T²-R^(2p); or two R^(p) on the same saturatedcarbon atom, taken together with the carbon atom to which they areattached, form an optionally substituted 3- to 6-membered spirocycliccycloaliphatic ring. The variables R^(1p), R^(2p), and T² have thevalues described below.

T² is a C₁₋₆ alkylene chain optionally substituted with R^(3a) orR^(3b).

Each R^(1p) independently is an optionally substituted aryl, heteroaryl,or heterocyclyl group.

Each R^(2p) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O) N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O) R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.

In some embodiments, Ring D is selected from the group consisting of:

-   -   each R^(p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR^(5x),        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y));    -   each R^(8p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR^(5x),        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)),        provided that R^(8p) is other than —OR^(5x) or        —N(R^(4x))(R^(4y)) when located at a position adjacent to a ring        oxygen atom, and further provided that when two R^(8p) are        attached to the same carbon atom, one must be selected from the        group consisting of fluoro, —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)),        and C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally        substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or two R^(8p) on the same carbon atom        together form ═O or ═C(R^(5x))₂; or two R^(8p) on the same        carbon atom are taken together with the carbon atom to which        they are attached to form a 3- to 6-membered spirocyclic ring;    -   s is 0, 1, 2, 3, or 4;    -   t is 0, 1, or 2; and    -   the variables R^(4x), R^(4y), R^(5x) have the values described        above for formula (I).

In some embodiments, each R^(8p) independently is selected from thegroup consisting of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); or two R^(8p) on the same carbon atom are takentogether with the carbon atom to which they are attached to form a 3- to6-membered spirocyclic ring; provided that R^(8p) is other than —OR^(5x)or —N(R^(4x))(R^(4y)) when located at a position adjacent to a ringoxygen atom; and

-   -   s is 0, 1, or 2.

Another embodiment of the invention relates to a compound of formula(I), wherein:

-   -   R^(g) is —N(R⁸)(R⁹);    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   R⁹ is hydrogen, C₁₋₄ aliphatic, -T³-R^(9a) or -T⁴-R^(9b);        -   T³ is a C₁₋₆ alkylene chain substituted with 0-2            independently selected R^(3a) or R^(3b);        -   T⁴ is a C₂₋₆ alkylene chain substituted with 0-2            independently selected R^(3a) or R^(3b);        -   R^(9a) is —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —S(O)R⁶, —SO₂R⁶,            —SO₂—N(R⁴)₂, —C(R⁵)═N—OR⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵,            —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, or —C(═NR⁴)—OR⁵; and        -   R^(9b) is halo, —NO₂, —CN, —OR⁵, —SR⁶, —N(R⁴)₂,            —N(R⁴)C(O)R⁵, —N(R⁴)C(O)N(R⁴)₂, —N(R⁴)CO₂R⁵, —O—CO₂—R⁵,            —OC(O)N(R⁴)₂, —OC(O)R⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)S(O)₂R⁶, or            —N(R⁴)SO₂—N(R⁴)₂.

In some such embodiments, R⁹ is hydrogen or a C₁₋₆ aliphatic or C₁₋₆fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)).

In a particular embodiment, the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

stereochemical configurations depicted at asterisked positions indicateabsolute stereochemistry; and

the variables Q, R^(a), R^(b), R^(c), R^(d), R^(g), R^(h), and R^(j)have the values and preferred values described above for formulae(I)-(VII).

In some embodiments, the invention relates to a subgenus of thecompounds of formula (VIII), characterized by formula (VIIIa):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R^(a) is —OH;    -   R^(b) and R^(d) are each independently hydrogen, fluoro, or C₁₋₄        aliphatic;    -   R^(c) is hydrogen, fluoro, or —OR^(5x);    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   each R^(p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR⁵,        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y));    -   each R^(8p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR⁵,        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)),        provided that R^(8p) is other than —OR^(5x) or        —N(R^(4x))(R^(4y)) when located at a position adjacent to a ring        oxygen atom, and further provided that when two R^(8p) are        attached to the same carbon atom, one must be selected from the        group consisting of fluoro, —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)),        and C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally        substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or two R^(8p) on the same carbon atom        together form ═O or ═C(R^(5x))₂;    -   R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted;    -   R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted, or an optionally substituted 5- or 6-membered aryl,        heteroaryl, or heterocyclyl ring; or    -   R^(4x) and R^(4y), taken together with the nitrogen atom to        which they are attached, form an optionally substituted 4- to        8-membered heterocyclyl ring having, in addition to the nitrogen        atom, 0-2 ring heteroatoms independently selected from N, O, and        S;    -   each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀        ar(C₁₋₄)alkyl;    -   s is 0, 1, 2, 3, or 4; and    -   t is 0, 1, or 2.

Subgenus definitions for Ring A and variables X, Y, R^(a), R^(b), R^(c),R^(d), R^(e), and R^(f) described for formula (I) also apply to formulae(II)-(VIII). Compounds embodying any combination of the preferred valuesfor the variables described herein are within the scope of the presentinvention.

Representative examples of compounds of formula (I) are shown in Table1.

TABLE 1 E1 Activating Enzyme Inhibitors

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

The compounds in Table 1 above may also be identified by the followingchemical names:

Chemical Name I-1((1S,2S,4R)-4-{4-[(2-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-2[(1S,2S,4R)-4-(4-{[2-(difluoromethoxy)benzyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-3[(1S,2S,4R)-2-hydroxy-4-(4-{methyl[(1S)-1-phenylethyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-4[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-5((1S,2S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methyl sulfamate I-6((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-7[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-8[(1S,2S,4R)-2-hydroxy-4-(4-{[4-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-9{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methyl sulfamate I-10((1S,2S,4R)-4-{4-[benzyl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-11((1S,3S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-12((1S,2S,4R)-4-{4-[(4S)-3,4-dihydro-2H-chromen-4-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-13((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-14[(1S,2S,4R)-4-(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-15((1S,2S,4R)-4-{4-[(2,6-difluorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-16((1S,2S,4R)-4-{4-[(3,5-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-17((1S,2R,3S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methyl sulfamate I-18[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-19((1S,2S,4R)-4-{4-[(2,4-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-20((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate I-21[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-22((1S,2R,3S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methyl sulfamate I-23((1S,2S,4R)-4-{6-[(4-chlorobenzyl)amino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methyl sulfamate I-24((1S,2S,4R)-4-{4-[(3,4-dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-25((1S,2S,4R)-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-26((1S,2S,4R)-4-{4-[(1,3-benzodioxol-5-ylmethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-27[(1S,2S,4R)-4-(4-{[(1S)-5-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-28{(1S,2S,4R)-2-hydroxy-4-[4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methyl sulfamate I-29((1S,2S,4R)-4-{4-[(cyclohexylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-30((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methyl sulfamate I-31{(1S,2S,4R)-4-[4-(benzylamino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methyl sulfamate I-32{(1S,2S,4R)-4-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methyl sulfamate I-33[(1S,2S,4R)-4-(4-{[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-34((1S,2S,4R)-4-{4-[(4-chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-35((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-36[(1S,2S,4R)-4-(4-{[(1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-37((1S,2S,4R)-2-hydroxy-4-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-38((1S,2S,4R)-2-hydroxy-4-{4-[(1-naphthylmethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-39[(1S,2S,4R)-4-(4-anilino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-40{(1S,2S,4R)-2-hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methyl sulfamate I-41[(1S,2S,4R)-2-hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-42[(1S,2S,4R)-4-(4-{[4-chloro-2-(trifluoromethyl)benzyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-43((1S,2S,4R)-2-hydroxy-4-{4-[(2-methoxybenzyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopentyl)methyl sulfamate I-44[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-45((1S,2S,4R)-4-{4-[(4-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-46[(1S,2S,4R)-2-hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-47[(1S,2S,4R)-2-hydroxy-4-(4-{[2-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-48((1S,2S,4R)-4-{4-[(4-chloro-2-methylbenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-49{(1S,2S,4R)-4-[4-(benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methyl sulfamate I-50{(1S,2S,4R)-2-hydroxy-4-[4-(2-methyl-2-phenylpropyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentyl}methyl sulfamate I-51((1S,2S,4R)-4-{4-[(3-chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-52[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-53{(1S,2R,3S,4R)-2,3-dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentyl}methyl sulfamate I-54[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate I-55((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methyl sulfamate I-56N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide I-57{(2S,3S,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3-hydroxytetrahydrofuran-2-yl}-methyl sulfamate I-58N-[((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methyl]sulfamide I-592-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide I-60((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxy-1-methylcyclopentyl)methyl sulfamate I-61[(1S,2S,4R)-4-(4-{[(1S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-62[(1S,2S,4R)-4-(4-{[(1S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-63[(1S,2S,4R)-4-(4-{[(1R)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-64[(1S,2S,4R)-4-(4-{[(1S)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-65[(1S,2S,4R)-4-(4-{[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-66[(1S,2S,4R)-4-(4-{[(1S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-67[(1S,2S,4R)-4-(4-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate I-68((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate I-69[(1S,2S,4R)-4-(5-fluoro-4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate I-70[(1S,2S,4R)-4-(4-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-71[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-72[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-73(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide I-74N-{[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl}sulfamideI-75N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide I-762-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethyl sulfamate I-77(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl sulfamate I-78(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl sulfamate I-79[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-(methoxymethyl)-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-80[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S,2S)-2-(methoxymethyl)-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-81[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-82[(1S,2S,4R)-2-hydroxy-4-(4-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-83[(1S,2S,4R)-4-(4-{[(1R,2R)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-84[(1S,2S,4R)-4-(4-{[(1S,2S)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl sulfamate I-85[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamateI-86((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-methoxycyclopentyl)methyl sulfamate

General Synthetic Methodology

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in Schemes 1-10 below, and in the Examples.

Scheme 1 above shows a general route for preparing compounds of formula(I), wherein Ring A has formula A-ii. Those of ordinary skill in the artwill recognize that compounds of formula (I) wherein Ring A is otherthan A-ii can be prepared by the same general route, beginning withappropriate starting materials analogous to i.

Methods for the synthesis of chloro-substituted pyrrolopyrimidines suchas formula i are known (P. Reigan et al., Bioorg. Med. Chem. Lett.,2004, 14, 5247-5250; J. Heterocyclic Chem., 1988, 25, 1633-1639). Asshown in Scheme 1, conversion of compounds of formula i to substitutedpyrrolopyrimidines is accomplished by coupling with the appropriatelysubstituted amines or mercaptans (see Pathak, A. K.; Pathak, V.; Seitz,L. E.; Suling, W. J.; Reynolds, R. C., J. Med. Chem. 2004, 47, 273-276)at elevated temperature in protic solvents, such as butanol orisopropanol, using an appropriate base, such as DIPEA or Et₃N (MethodA). Alternatively, pyrrolopyrimidines i can be coupled with anappropriately substituted alcohol in H₂O in the presence of a base, suchas KOH, at refluxing temperatures (Method B). Compounds of formula i canalso be treated with Grignard reagents in the presence of ferricacetylacetonate in THF (Method C) to provide carbon-substitutedpyrrolopyrimidines. Compounds iv are prepared from ii by the opening ofepoxide iii with a suitable base, such as NaH, LiHMDS, or cesiumcarbonate, at elevated temperatures in DMF (Method D).

For preparation of compounds of formula (I), wherein R^(c) and R^(d) areeach hydrogen, deoxygenation can be effected at this stage. Thus,alkylation of compounds of formula iv to provide xanthates v is effectedby treatment with chlorophenylthionocarbonate and a suitable base, suchas DMAP, in DCM (Method E). Deoxygenation of compounds of formula v isachieved by treatment with a radical source, such as Bu₃SnH, and aradical initiator, such as AIBN, in refluxing toluene (Method F).Subsequent deprotection with an aqueous acid, such as AcOH (Method G),provides compounds of formula vii.

The primary alcohol of the diols of formula vii is selectivelyprotected, e.g., with a bulky silyl protecting group such as TBDMS.Subsequent treatment with acetic anhydride affords the protectedalcohols of formula viii (Method H). Selective deprotection of theprimary alcohol using a fluoride reagent, such as pyridinehydrofluoride, in a basic solvent, such as pyridine, provides compoundsof formula ix (Method I). Further treatment with freshly preparedchlorosulfonamide x affords the penultimate sulfamates xi (Method J).Acetate removal by treatment with a base, such as ammonia, in MeOHaccording to Method K yields compounds of formula xii.

Compounds of formula (I), wherein R^(g) is —N(R⁴)₂ may be prepared by analternative procedure in which a later stage intermediate incorporatinga leaving group such as a sulfone is directly displaced by a substitutedamine. As shown in Scheme 2, treatment of compounds of formula i withbenzylmercaptan under conditions described in Method B providesbenzylsulfanyl pyrrolopyrimidines of formula xiii. Subsequent treatmentwith the conditions outlined in Methods D-F affords compounds of formulaxiv. Compounds xiv are reacted with an oxidizing agent, such as m-CPBA,in DCM in the presence of a base, such as sodium bicarbonate, to providesulfones of formula xv (Method L).

Compounds of formula xvi are then synthesized by treatment of xv with anappropriately substituted amine using a base, such as DIPEA, in ahigh-boiling protic solvent, such as EtOH, at elevated temperatures(Method M) similar to literature procedures (Lin, X.; Robins, M. J.,Organic Lett. 2000, 2, 3497-3499). Removal of the protecting group isaccomplished in a manner analogous to that depicted in Scheme 1, usingthe procedure described in Method G, to give diols of formula xvii.Methods for the synthesis of tert-butyl chlorosulfonylcarbamate xviiiare known (Hirayama et al., Biorg. Med. Chem., 2002, 10, 1509-1523), andthis reagent is reacted selectively with the primary alcohol using ahindered base, such as 2,6-di-tert-butyl-4-methylpyridine, in a solvent,such as AcCN, to afford Boc sulfamates of formula xix (Method N).TFA-deprotection according to Method O yields the compounds of formulaxx. The conversion of compounds xv to xvi has the potential advantage ofbeing amenable to solution phase library synthesis.

Methods for the synthesis of the intermediate alkene diol xxi are known(Nucleosides, Nucleotides & Nucleic Acids, 2002, 21, 65-72). Upontreatment with m-CPBA, diol xxi is converted to epoxy diol xxvii.Subsequent protection of the diol using p-anisaldehyde dimethyl acetalprovides epoxide iii. Alternatively, TBDPS-protection of the primaryalcohol of xxi followed by PDC oxidation gives the α,β-unsaturatedketone xxii. Addition of MeLi to the ketone in Et₂O gives tertiaryalcohol xxiii, and treatment with TBAF in THF provides diol xxiv.Epoxidation and diol protection affords the protected substitutedepoxide xxvi.

The aminoindans used for the preparation of 4-aminoindanyl compounds offormula xxx are either commercially available, or they are preparedthrough the literature methods highlighted in Scheme 4. Appropriatelysubstituted indanones of formula xxviii are treated with(R)-2-amino-2-phenylethanol to provide the desired intermediate imine.Subsequent reaction with an appropriate reducing agent, such as sodiumborohydride in the presence of AcOH, gives amino alcohols of formulaxxix (Method P). Treatment with lead tetraacetate, followed by refluxingin HCl, gives aminoindans of formula xxx (Method Q). One skilled in theart will recognize that the use of (S)-2-amino-2-phenylethanol in MethodP can be used to afford the opposite enantiomer of indan xxx.

Compounds of formula (I), wherein R^(c) is —OR⁵ can be prepared asoutlined in Scheme 5. Thus, compounds of formula iv, as prepared inScheme 1, are directly converted to triols of formula xxxi (Method G).Protection of the two secondary alcohols with 2,2-dimethoxypropane andan acid catalyst, such as p-TSA monohydrate, in acetone affordsisopropylidenes xxxii (Method R). Further reaction withchlorosulfonamide x by Method J, as described in Scheme 1, affordssulfamates of formula xxxiii. Removal of the isopropylidene using anacid, such as TFA, in the presence of water yields compounds of formulaxxxiv (II-C), according to Method S. Alternatively, triol xxxi can beselectively sulfamoylated at the primary hydroxyl and deprotected asdescribed in Scheme 2, Methods N-O to give compounds of formula xxxiv.

Compounds of formula xxxv are prepared by the methods described inScheme 1. Treatment of benzylamines xxxv with an aqueous acid, such asAcOH, affords amines xxxvi (Method G). Selective protection of theprimary alcohol using TBDMSCl and an appropriate base, such asimidazole, in DMF gives compounds of formula xxxvii (Method T).Bis-acylation is effected by treatment with appropriately substitutedacylating reagent of formula xxxviii (X=Cl, OH, —OC(O)R⁵) and anappropriate base, such as pyridine, to afford compounds of formula xxxix(Method U). Subjecting compounds xxxix to the conditions described inMethods I-K affords both the fully deprotected analogs xl as well asamides xli.

Compounds of formula (I) wherein R^(a) and R^(c) together form a bond,and compounds of formula (I) wherein each of R^(a)-R^(d) is hydrogen,can be prepared as outlined in Scheme 7. Triols of formula xlii areprepared following the procedure in Scheme 5. The primary alcohol isselectively protected to give the diols of formula xliii (Method T),which are then alkylated by 1,1′-thiocarbonyldiimidazole in a suitablesolvent, such as DMF, to yield dioxole-thiones xliv (Method U).Treatment with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine in anappropriate solvent, such as THF, affords alkenes of formula xlv (MethodV), which are exposed to the conditions outlined in Methods I-J toafford sulfamates xlvi. Hydrogenation under an atmosphere of hydrogen inthe presence of a catalyst, such as palladium on carbon, in EtOAc givessaturated sulfamates of formula xlvii (Method W).

Compounds of formula (I) wherein R^(k) is other than hydrogen areprepared as outlined in Schemes 8-9. Conversion of i to fluoro chloropyrrolopyrimidine xlvii is effected by treatment with Selectfluor™(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)) and AcOH in AcCN. Compound xlviii is thensubstituted with the appropriate substituents according to Methods A-Cand carried on to compounds of formula (I) according to Scheme 1.

Compounds of formula xlix are prepared as shown in Scheme 1, and areconverted to iodide l by treatment with NIS (Method X). Iodide 1 can beconverted to compounds of formula li using a variety ofpalladium-catalyzed coupling conditions, such as Sonagashira coupling(CuI, PdCl₂(PPh₃)₂, DIPEA, R^(i)C≡CH, Method Y). Following the methodsshown in Scheme 1, compounds of formula li are converted to finalcompounds of formula (I).

Compounds of formula (I) wherein Y is —O— can be prepared from compoundslviii. The synthesis of compounds of formula lviii is reported in theliterature (Ugarkar, B. G.; Castellino, A. J.; DaRe, J. S.;Ramirez-Weinhouse, M.; Kopcho, J. J.; Rosengren, S.; Erion, M. D., J.Med. Chem., 2003, 46, 4750-4760), and is outlined in Scheme 10. Methodsfor the conversion of D-ribose to lii are known (Inokawa, S.; Kitagawa,H.; Seo, K.; Yoshida, H.; Ogata, T., Carbohydr. Hydr. Res., 1973, 30,127-132). Hydroboration-oxidation using borane-THF complex affords liii,which is globally deprotected using sulfuric acid. Tetraol liv isprotected using 2,2-dimethoxypropane and subsequent protection of theprimary alcohol using TBDMS-Cl gives alcohol lvi. Selective chlorinationusing CCl₄ and HMPT in toluene affords the single enantiomer lvii.Glycosylation using compounds of formula i gives intermediates offormula lviii, which can be further elaborated as described in Schemes1, 2, and 6 above.

Compounds of formula (I) wherein X is CH₂ can be prepared from compoundsvii. As shown in Scheme 11, diol vii is protected as a bis-TBDMS etherlix using TBDMS-Cl, suitable base, such as triethylamine, and 4-DMAP(Method Z). Selective deprotection of primary TBDMS group to lx iseffected using aqueous acetic acid at elevated temperature (Method AA).Aldehyde lxi is obtained by oxidation of alcohol lx using TPAP and asuitable oxidant, such as NMO (method AB). Treatment of aldehyde lxiwith (diethoxyphosphoryl)-methanesulfonic acid ethyl ester and n-BuLi(Method AC) gives alkene lxii, which is in turn reduced to sulfonylester lxiii using a suitable reducing agent, such as sodium borohydridein ethanol (Method AD). Hydrolysis of the former ester using TBAI undermicrowave conditions (Method AE) gives sulfonic acid lxiv, which istransformed into protected sulfonamide lxv via intermediate sulfonylchloride (using thionyl chloride and then ammonia in dioxane, MethodAF). TBDMS deprotection using a suitable reagent, such as TBAF in THF(Method AG) affords sulfonamide lxvi.

Compounds of formula (I) wherein X is —CH═ can be prepared fromcompounds lxi. As shown in Scheme 12,tert-butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate is treatedwith n-BuLi and the formed reagent is mixed with aldehyde lxi (MethodAH) to give protected vinyl sulfonamide lxvi. The Boc group isdeprotected using a suitable Lewis acid, such as ZnBr₂ (Method AI) toafford lxvii. The final deprotection of a TBDMS group is carried outusing a suitable reagent, such as TBAF in THF (Method AJ) to givelxviii.

Compounds of formula (I) wherein X is NH can be prepared from compoundslx. As shown in Scheme 13, alcohol lx is treated with N-Boc-sulfonamideunder Mitsunobu conditions, such as triphenylphosphine and DEAD in ethylacetate under elevated temperature to afford protected sulfamide lxix(Method AK). The TBDMS group is deprotected using a suitable acid, suchas aqueous HCl (Method AL) to afford lxx. The final deprotection of aBoc group is carried out using a suitable reagent, such as TFA inmethylene chloride (Method AM) to give lxxi.

Compounds of formula (I) wherein X is —N(CH₃)— can be prepared fromcompounds lxix. As shown in Scheme 14, sulfamide lxix is reduced with asuitable agent, such as LiAlH₄ in THF under elevated temperature toafford protected N-methyl sulfamide lxxii (Method AN). The TBDMS groupis deprotected using a suitable acid, such as aqueous HCl (Method AL) toafford lxxiii.

Compounds of formula (I) wherein X is O and m=2 can be prepared fromcompounds lx. As shown in Scheme 15, alcohol lx is transformed to asuitable leaving group, such as mesylate lxxix, using methanesulfonylchloride and an appropriate base, such as triethylamine in DCM (MethodAO). The formed mesylate is displaced with a nitrile group using asuitable nucleophile, such as sodium cyanide in DMSO under elevatedtemperature (Method AP) to afford nitrile lxxx, which is reduced toaldehyde lxxxi using a suitable reducing agent, such as DIBAL in DCM(Method AQ). Further reduction of lxxxi using a suitable reagent, suchas sodium tetrahydroborate in methanol affords alcohol lxxxii (MethodAR). Treatment of lxxxii with a sulfamating reagent, such aschlorosulfonamide in acetonitrile in a presence of an appropriate base,such as triethylamine affords protected sulfamate lxxxiii (Method J).TBDMS removal by treatment with an acid, such as HF.pyridine, inpyridine/THF according to Method AS yields compounds of formula lxxxiv.

Compounds of formula (I) wherein X is O and m=0 can be prepared from3-cyclopentene-1-ol (lxxxv). As shown in Scheme 16, alcohol lxxxv isactivated by transformation to a suitable leaving group, such asmesylate lxxxvi using methanesulfonyl chloride and an appropriate base,such as pyridine and DMAP in DCM (Method AT). Treatment of mesylatelxxxvi with base lxxxvii in the presence of cesium carbonate in DMFunder elevated temperature (Method AU) affords lxxxviii. Treatment ofalkene lxxxviii with an appropriate chiral dihydroxylation agent, suchas AD-mix-α (Sigma-Aldrich) in tert-butyl alcohol (Method AV) gives diollxxxix, which upon sulfamation with chlorosulfonamide as described inMethod J affords a diastereoisomeric mixture of sulfamates xc and xci(Method AW).

The invention further provides synthetic intermediates useful for thepreparation of the compounds of formula (I). In one embodiment, theinvention provides a compound of formula (IX):

wherein:

depicted stereochemical configurations indicate absolutestereochemistry;

R^(b) is fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

R^(aa) and R^(bb) are each independently hydrogen or a hydroxylprotecting group, or R^(aa) and R^(bb) together form a cyclic diolprotecting group; and

the variables R^(d), R^(e), and R^(f) have the values and preferredvalues described above for formula (I).

As used herein, the term “hydroxyl protecting group” refers to achemical group that i) reacts with a hydroxyl functional group of asubstrate to form a protected substrate; ii) is stable to reactionconditions to which the protected substrate will be subjected; and iii)is removable from a protected substrate to liberate the hydroxylfunctional group under conditions that are compatible with otherfunctionality present in the substrate. The hydroxyl groups of 1,2- and1,3-diols may be individually protected or may be jointly protected witha cyclic diol protecting group. Examples of suitable hydroxyl protectinggroups and diol protecting groups may be found in T. W. Greene and P. G.M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley &Sons Inc., NY (1999).

In a particular embodiment, the compound of formula (VIII) isrepresented by the formula:

The invention also provides a compound of formula (X):

wherein:

depicted stereochemical configurations indicate absolutestereochemistry;

R^(aa) is hydrogen or a hydroxyl protecting group; and

R^(bb) is hydrogen or a hydroxyl protecting group; or

R^(aa) and R^(bb) together form a cyclic diol protecting group; and

the variables R^(b), R^(d), R^(e), and R^(f) have the values andpreferred values described above for formula (I).

In one embodiment, the compound of formula (X) is characterized byformula (Xa):

wherein Ar is an optionally substituted aryl group. In some embodiments,Ar is an optionally substituted phenyl group. In certain embodiments, Aris para-methoxy-phenyl.

In certain particular embodiments, the compound of formula (Xa) isselected from the group consisting of:

wherein A is as described above for formula (Xa).

The invention also provides a compound of formula (XI) or formula (XII):

wherein:

depicted stereochemical configurations indicate absolutestereochemistry;

R^(aa) is hydrogen or a hydroxyl protecting group; and

R^(bb) is hydrogen or a hydroxyl protecting group;

R^(cc) is hydrogen or a hydroxyl protecting group; or

R^(aa) and R^(bb) together form a cyclic diol protecting group; or

R^(aa) and R^(cc) together form a cyclic diol protecting group; and

Ring A and the variables R^(b), R^(d), R^(e), and R^(f) have the valuesand preferred values described above for formula (I).

In some embodiments, the compound is characterized by formula (XIa) or(XIIa)

In certain embodiments, the invention relates to a compound selectedfrom the group consisting of:

In certain other embodiments, the invention relates to a compoundselected from the group consisting of:

wherein R^(aa) and R^(cc) are each independently a hydroxyl protectinggroup, or R^(aa) and R^(cc) together form a cyclic diol protectinggroup.

In certain other embodiments, the invention relates to a compoundselected from the group consisting of:

wherein R^(aa) and R^(bb) are each independently a hydroxyl protectinggroup. In some embodiments, R^(aa) and R^(bb) are selected so as toallow selective protection and deprotection. In certain embodiments,R^(a)a is an acyl protecting group, and R^(bb) is a silyl protectinggroup. In a particular embodiment, R^(aa) is acetyl or substitutedacetyl, and R^(bb) is tert-butyldimethylsilyl ortert-butyldiphenylsilyl.

Uses of Compounds of the Invention

The compounds of this invention are useful inhibitors of E1 enzymeactivity. In particular, the compounds are designed to be inhibitors ofNAE, UAE, and/or SAE. Inhibitors are meant to include compounds whichreduce the promoting effects of E1 enzymes in ubl conjugation to targetproteins (e.g., reduction of ubiquitination, neddylation, sumoylation),reduce intracellular signaling mediated by ubl conjugation, and/orreduce proteolysis mediated by ubl conjugation (e.g., inhibition ofcullin-dependent ubiquitination and proteolysis (e.g., theubiquitin-proteasome pathway)). Thus, the compounds of this inventionmay be assayed for their ability to inhibit the E1 enzyme in vitro or invivo, or in cells or animal models according to methods provided infurther detail herein, or methods known in the art. The compounds may beassessed for their ability to bind or mediate E1 enzyme activitydirectly. Alternatively, the activity of compounds may be assessedthrough indirect cellular assays, or assays of downstream effects of E1activation to assess inhibition of downstream effects of E1 inhibition(e.g., inhibition of cullin-dependent ubiquitination and proteolysis).For example, activity may be assessed by detection of ubl-conjugatedsubstrates (e.g., ubl-conjugated E2s, neddylated cullins, ubiquitinatedsubstrates, sumoylated substrates); detection of downstream proteinsubstrate stabilization (e.g., stabilization of p27, stabilization ofIκB); detection of inhibition of UPP activity; detection of downstreameffects of protein E1 inhibition and substrate stabilization (e.g.,reporter assays, e.g., NFκB reporter assays, p27 reporter assays).Assays for assessing activities are described below in the Experimentalsection and/or are known in the art.

One embodiment of this invention relates to a composition comprising acompound of this invention or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. It will beappreciated that the compounds of this invention may be derivatized atfunctional groups to provide prodrug derivatives which are capable ofconversion back to the parent compounds in vivo. Examples of suchprodrugs include the physiologically acceptable and metabolically labileester derivatives, such as methoxymethyl esters, methylthiomethylesters, or pivaloyloxymethyl esters derived from a hydroxyl group of thecompound or a carbamoyl moiety derived from an amino group of thecompound. Additionally, any physiologically acceptable equivalents ofthe present compounds, similar to the metabolically labile esters orcarbamates, which are capable of producing the parent compoundsdescribed herein in vivo, are within the scope of this invention.

If pharmaceutically acceptable salts of the compounds of the inventionare utilized in these compositions, the salts preferably are derivedfrom inorganic or organic acids and bases. For reviews of suitablesalts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) andRemington: The Science and Practice of Pharmacy, 20th Ed., ed. A.Gennaro, Lippincott Williams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

In some embodiments, the invention relates to an acid addition salt of acompound of formula I formed by protonation of a basic moiety in themolecule. In certain such embodiments, the invention relates to ahydrochloride salt of a compound of formula I.

In some other embodiments, the invention relates to a base addition saltof a compound of formula I formed by deprotonation of the sulfamate(X=O) moiety, the sulfamide (X=NH) moiety, or the sulfonamide (X=CH₂)moiety, as applicable. In some such embodiments, the invention relatesto a sodium or potassium salt of a compound of formula I.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The term “pharmaceutically acceptable carrier” is used herein to referto a material that is compatible with a recipient subject, preferably amammal, more preferably a human, and is suitable for delivering anactive agent to the target site without terminating the activity of theagent. The toxicity or adverse effects, if any, associated with thecarrier preferably are commensurate with a reasonable risk/benefit ratiofor the intended use of the active agent.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, solubilizing agents,bioavailability modifiers and combinations of these.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates or carbonates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intraperitoneal, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intravenously, or subcutaneously.The formulations of the invention may be designed to be short-acting,fast-releasing, or long-acting. Still further, compounds can beadministered in a local rather than systemic means, such asadministration (e.g., by injection) at a tumor site.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as, but not limited to, an oil, water, analcohol, and combinations of these. Solubilizing agents such ascyclodextrins may be included. Pharmaceutically suitable surfactants,suspending agents, or emulsifying agents, may be added for oral orparenteral administration. Suspensions may include oils, such as but notlimited to, peanut oil, sesame oil, cottonseed oil, corn oil and oliveoil. Suspension preparation may also contain esters of fatty acids suchas ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. Whenaqueous suspensions are required for oral use, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening, flavoring or coloring agents may also be added. For oraladministration in a capsule form, useful diluents include lactose anddried cornstarch. In the case of tablets for oral use, carriers that arecommonly used include lactose and corn starch. Lubricating agents, suchas magnesium stearate, are also typically added. Coatings may be usedfor a variety of purposes; e.g., to mask taste, to affect the site ofdissolution or absorption, or to prolong drug action. Coatings may beapplied to a tablet or to granulated particles for use in a capsule.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The pharmaceutical compositions of this invention are particularlyuseful in therapeutic applications relating to disorders as describedherein (e.g., proliferation disorders, e.g., cancers, inflammatory,neurodegenerative disorders). Preferably, the composition is formulatedfor administration to a patient having or at risk of developing orexperiencing a recurrence of the relevant disorder being treated. Theterm “patient”, as used herein, means an animal, preferably a mammal,more preferably a human. Preferred pharmaceutical compositions of theinvention are those formulated for oral, intravenous, or subcutaneousadministration. However, any of the above dosage forms containing atherapeutically effective amount of a compound of the invention are wellwithin the bounds of routine experimentation and therefore, well withinthe scope of the instant invention. In certain embodiments, thepharmaceutical composition of the invention may further comprise anothertherapeutic agent. Preferably, such other therapeutic agent is onenormally administered to patients with the disorder, disease orcondition being treated.

By “therapeutically effective amount” is meant an amount of compound orcomposition sufficient, upon single or multiple dose administration, tocause a detectable decrease in E1 enzyme activity and/or the severity ofthe disorder or disease state being treated. “Therapeutically effectiveamount” is also intended to include an amount sufficient to treat acell, prolong or prevent advancement of the disorder or disease statebeing treated (e.g., prevent additional tumor growth of a cancer,prevent additional inflammatory response), ameliorate, alleviate,relieve, or improve a subject's symptoms of the a disorder beyond thatexpected in the absence of such treatment. The amount of E1 enzymeinhibitor required will depend on the particular compound of thecomposition given, the type of disorder being treated, the route ofadministration, and the length of time required to treat the disorder.It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, and diet of the patient, time ofadministration, rate of excretion, drug combinations, the judgment ofthe treating physician, and the severity of the particular disease beingtreated. In certain aspects where the inhibitor is administered incombination with another agent, the amount of additional therapeuticagent present in a composition of this invention typically will be nomore than the amount that would normally be administered in acomposition comprising that therapeutic agent as the only active agent.Preferably, the amount of additional therapeutic agent will range fromabout 50% to about 100% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent.

One embodiment of the invention relates to a method of inhibiting ordecreasing E1 enzyme activity in a sample comprising contacting thesample with a compound of this invention, or composition comprising acompound of the invention. The sample, as used herein, includes, withoutlimitation, sample comprising purified or partially purified E1 enzyme,cultured cells or extracts of cell cultures; biopsied cells or fluidobtained from a mammal, or extracts thereof; and body fluid (e.g.,blood, serum, saliva, urine, feces, semen, tears) or extracts thereof.Inhibition of E1 enzyme activity in a sample may be carried out in vitroor in vivo, in cellulo, or in situ.

In another embodiment, the invention provides a method for treating apatient having a disorder, a symptom of a disorder, at risk ofdeveloping or experiencing a recurrence of a disorder, comprisesadministering to the patient a compound or pharmaceutical compositionaccording to the invention. Treating can be to cure, heal, alleviate,relieve, alter, remedy, ameliorate, palliate, improve or affect thedisorder, the symptoms of the disorder or the predisposition toward thedisorder. While not wishing to be bound by theory, treating is believedto cause the inhibition of growth, ablation, or killing of a cell ortissue in vitro or in vivo, or otherwise reduce capacity of a cell ortissue (e.g., an aberrant cell, a diseased tissue) to mediate adisorder, e.g., a disorder as described herein (e.g., a proliferativedisorder, e.g., a cancer, inflammatory disorder). As used herein,“inhibiting the growth” or “inhibition of growth” of a cell or tissue(e.g., a proliferative cell, tumor tissue) refers to slowing,interrupting, arresting or stopping its growth and metastases and doesnot necessarily indicate a total elimination of growth.

Disease applications include those disorders in which inhibition of E1enzyme activity is detrimental to survival and/or expansion of diseasedcells or tissue (e.g., cells are sensitive to E1 inhibition; inhibitionof E1 activity disrupts disease mechanisms; reduction of E1 activitystabilizes protein which are inhibitors of disease mechanisms; reductionof E1 activity results in inhibition of proteins which are activators ofdisease mechanisms). Disease applications are also intended to includeany disorder, disease or condition which requires effective cullinand/or ubiquitination activity, which activity can be regulated bydiminishing E1 enzyme activity (e.g., NAE, UAE activity).

For example, methods of the invention are useful in treatment ofdisorders involving cellular proliferation, including, but not limitedto, disorders which require an effective cullin-dependent ubiquitinationand proteolysis pathway (e.g., the ubiquitin proteasome pathway) formaintenance and/or progression of the disease state. The methods of theinvention are useful in treatment of disorders mediated via proteins(e.g., NFκB activation, p27^(Kip) activation, p21^(WAF/CIP1) activation,p53 activation) which are regulated by E1 activity (e.g., NAE activity,UAE activity, SAE activity). Relevant disorders include proliferativedisorders, most notably cancers and inflammatory disorders (e.g.,rheumatoid arthritis, inflammatory bowel disease, asthma, chronicobstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g.,atopic dermatitis, psoriasis), vascular proliferative disorders (e.g.,atherosclerosis, restenosis) autoimmune diseases (e.g., multiplesclerosis, tissue and organ rejection)); as well as inflammationassociated with infection (e.g., immune responses), neurodegenerativedisorders (e.g., Alzheimer's disease, Parkinson's disease, motor neuronedisease, neuropathic pain, triplet repeat disorders, astrocytoma, andneurodegeneration as result of alcoholic liver disease), ischemic injury(e.g., stroke), and cachexia (e.g., accelerated muscle protein breakdownthat accompanies various physiological and pathological states, (e.g.,nerve injury, fasting, fever, acidosis, HIV infection, canceraffliction, and certain endocrinopathies)).

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers.

In some embodiments, the cancer is a solid tumor. Non-limiting examplesof solid tumors that can be treated by the methods of the inventioninclude pancreatic cancer; bladder cancer; colorectal cancer; breastcancer, including metastatic breast cancer; prostate cancer, includingandrogen-dependent and androgen-independent prostate cancer; renalcancer, including, e.g., metastatic renal cell carcinoma; hepatocellularcancer; lung cancer, including, e.g., non-small cell lung cancer(NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of thelung; ovarian cancer, including, e.g., progressive epithelial or primaryperitoneal cancer; cervical cancer; gastric cancer; esophageal cancer;head and neck cancer, including, e.g., squamous cell carcinoma of thehead and neck; melanoma; neuroendocrine cancer, including metastaticneuroendocrine tumors; brain tumors, including, e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma; bone cancer; and soft tissue sarcoma.

In some other embodiments, the cancer is a hematologic malignancy.Non-limiting examples of hematologic malignancy include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the compound or composition of the invention isused to treat a patient having or at risk of developing or experiencinga recurrence in a cancer selected from the group consisting ofcolorectal cancer, ovarian cancer, lung cancer, breast cancer, gastriccancer, prostate cancer, and pancreatic cancer. In certain preferredembodiments, the cancer is selected from the group consisting of lungcancer, colorectal cancer, ovarian cancer and a hematologic cancer.

Depending on the particular disorder or condition to be treated, in someembodiments, the E1 enzyme inhibitor of the invention is administered inconjunction with additional therapeutic agent or agents. In someembodiments, the additional therapeutic agent(s) is one that is normallyadministered to patients with the disorder or condition being treated.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disorder or condition are known as“appropriate for the disorder or condition being treated.”

The E1 inhibitor of the invention may be administered with the othertherapeutic agent in a single dosage form or as a separate dosage form.When administered as a separate dosage form, the other therapeutic agentmay be administered prior to, at the same time as, or followingadministration of the E1 inhibitor of the invention.

In some embodiments, the E1 enzyme inhibitor of the invention isadministered in conjunction with a therapeutic agent selected from thegroup consisting of cytotoxic agents, radiotherapy, and immunotherapyappropriate for treatment of proliferative disorders and cancer.Non-limiting examples of cytotoxic agents suitable for use incombination with the E1 enzyme inhibitors of the invention include:antimetabolites, including, e.g., capecitibine, gemcitabine,5-fluorouracil or 5-fluorouracil/leucovorin, fludarabine, cytarabine,mercaptopurine, thioguanine, pentostatin, and methotrexate;topoisomerase inhibitors, including, e.g., etoposide, teniposide,camptothecin, topotecan, irinotecan, doxorubicin, and daunorubicin;vinca alkaloids, including, e.g., vincristine and vinblastin; taxanes,including, e.g., paclitaxel and docetaxel; platinum agents, including,e.g., cisplatin, carboplatin, and oxaliplatin; antibiotics, including,e.g., actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin,idarubicin, doxorubicin and pegylated liposomal doxorubicin; alkylatingagents such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine, andcyclophosphamide; including, e.g., CC-5013 and CC-4047; protein tyrosinekinase inhibitors, including, e.g., imatinib mesylate and gefitinib;proteasome inhibitors, including, e.g., bortezomib, thalidomide andrelated analogs; antibodies, including, e.g., trastuzumab, rituximab,cetuximab, and bevacizumab; mitoxantrone; dexamethasone; prednisone; andtemozolomide.

Other examples of agents the inhibitors of the invention may be combinedwith include anti-inflammatory agents such as corticosteroids, TNFblockers, II-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporine,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, methotrexate, andsulfasalazine; antibacterial and antiviral agents; and agents forAlzheimer's treatment such as donepezil, galantamine, memantine andrivastigmine.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES Abbreviations

AA ammonium acetateAcOH acetic acidAcCN acetonitrileAIBN 2,2′-azobisisobutyronitrileBoc tert-butoxycarbonylDCM dichloromethaneDEAD diethyl azodicarboxylateDIBAL diisobutylaluminum hydride

DIPEA N,N-diisopropylethylamine

DMAP N,N-dimethyl-4-aminopyridineDMF dimethylformamideEtOAc ethyl acetateEtOH ethanolFA formic acidh hoursKO-t-Bu potassium tert-butoxideLC/MS liquid chromatography mass spectrumLiHMDS lithium bis(trimethylsilyl)amidem-CPBA meta-chloroperbenzoic acidMeOH methanolMgSO₄ magnesium sulfatemin minutesMS mass spectrumMWI microwave irradiation

NIS N-iodosuccinimide NMO N-methylmorpholine-N-oxide

rt room temperatureTBAF tetra-n-butylammonium fluorideTBAI tetra-n-butylammonium iodideTB DMS tert-butyldimethylsilylTFA trifluoroacetic acidTHF tetrahydrofuranTPAP tetrapropylammonium perruthenate

Analytical LC-MS Methods

Spectra were run on a Phenominex Luna 5 μm C18 50×4.6 mm column on aHewlett-Packard HP1100 at 2.5 mL/min for a 3 minute run using thefollowing gradients:

-   -   Formic Acid Standard (FA Standard): Acetonitrile containing zero        to 100 percent 0.1% formic acid in water.    -   Ammonium Acetate Standard (AA Standard): Acetonitrile containing        zero to 100 percent 10 mM AA in water.

Example 1: ((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-35) Step a:(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol

(1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) wasdissolved in DCM (143 mL) and the solution was cooled to 0° C.3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixturewas stirred at rt for 4 h. TLC indicated complete conversion. Silica gel(20 g) was added, the mixture was concentrated to dryness and waspurified via silica gel chromatography eluting with a gradient of 0 to100% EtOAc in DCM to afford the title compound (2.75 g, 76%). LC/MS:R_(t)=0.37 min, ES⁺ 131 (AA standard).

Step b:(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d]-[1,3]dioxine

(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol (3.65 g,21.0 mol) was dissolved in DCM (121 mL) and the solution was cooled to0° C. 1-(Dimethoxymethyl)-4-methoxybenzene (10.7 mL, 63.1 mmol) wasadded followed by pyridinium p-toluenesulfonate (530 mg, 2.11 mmol). Themixture was stirred at rt overnight. TLC indicated complete conversion.The reaction mixture was concentrated in vacuo and the residue waspurified via silica gel chromatography eluting with a gradient of 0 to50% EtOAc in hexanes to afford the title compound (4.10 g, 78%). LC/MS:R_(t)=1.68 min, ES⁺ 249 (AA standard).

Step c:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol) was dissolvedin 1-butanol (60.0 mL) and N,N-diisopropylethylamine (3.57 mL, 20.5mmol) was added followed by (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol).The mixture was heated to reflux for 60 h, cooled down to rt and thesolvent was evaporated to dryness. The residue was purified via silicagel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM toafford the title compound (2.72 g, 80%). LC/MS: R_(t)=1.42 min, ES⁺ 251(AA standard).

Step d:(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamio]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol

N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(3.70 g, 14.8 mmol) was dissolved in DMF (49.4 mL) under an atmosphereof nitrogen. Sodium hydride (546 mg, 13.6 mmol) was added and thesuspension was stirred at 70° C. for 10 min to give a clear solution.(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(2.82 g, 11.4 mmol) dissolved in DMF (35.3 mL) was added to the solutionabove and the reaction was stirred at 110° C. for 2 h. The reactionmixture was cooled down, quenched with saturated aqueous sodium chloridesolution (30 mL), extracted with EtOAc (3×50 mL), dried with MgSO₄,filtered, and evaporated under high vacuum. The residue was purified viasilica gel chromatography eluting with a gradient of 30 to 100% EtOAc inhexanes to afford the title compound (3.90 g, 69%). LC/MS: R_(t)=1.86min, ES⁺ 500. (AA standard).

Step e:O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocclopenta[d][1,3]dioxin-7-yl]O-phenyl thiocarbonate

(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol(4.00 g, 8.02 mmol) was dissolved in DCM (169 mL) under an atmosphere ofargon and 4-(dimethylamino)-pyridine (2.94 g, 24.1 mmol) was addedfollowed by phenyl chlorothionocarbonate (2.22 mL, 16.0 mmol). Themixture was stirred at rt for 1 hour. The solvent was concentrated invacuo and purified via silica gel chromatography eluting with a gradientof 20 to 100% EtOAc in hexanes on a column pre-treated with 1% TEA inhexanes to afford the title compound (5.00 g, 99%). LC/MS: R_(t)=2.34min, ES⁺ 636 (AA standard).

Step f:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenyl thiocarbonate (5.00 g, 7.88 mmol) was dissolved in toluene (150mL) under an atmosphere of nitrogen and tri-n-butyltin hydride (4.24 mL,15.8 mmol) was added followed by 2,2′-azo-bis-isobutyronitrile (259 mg,1.58 mmol). The solution was heated to reflux for 30 min, the mixturewas cooled down, the solvent was concentrated to 30 mL and the residuewas purified via silica gel chromatography eluting with a gradient of 30to 100% EtOAc in hexanes to afford the title compound (3.00 g, 79%).LC/MS: R_(t)=2.12 min, ES⁺ 483 (AA standard).

Step g:(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol

N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(3.00 g, 5.90 mmol) was dissolved in THF (11.6 mL), water (11.6 mL) andAcOH (34.9 mL, 614 mmol) were added. The mixture was stirred at rt underan atmosphere of argon for 60 h. The mixture was concentrated underreduced pressure and the residue was purified via silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM to affordthe title compound (2.10 g, 98%). LC/MS: R_(t)=1.46 min, ES⁺ 365 (AAstandard).

Step h:(1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentylacetate

(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol(3.00 g, 8.23 mmol), 1H-imidazole (1.68 g, 24.7 mmol) and4-(dimethylamino)-pyridine (100 mg, 0.818 mmol) were dissolved in DMF(90.0 mL) under an atmosphere of argon and the solution was cooled to 0°C. tert-Butyldimethylsilyl chloride (1.24 g, 8.23 mmol) was added andthe mixture was stirred at rt for 2 h. LC/MS indicated completeconversion. The reaction was quenched with saturated aqueous sodiumchloride solution (30 mL), extracted with EtOAc (3×50 mL), dried withMgSO₄, filtered, and concentrated in vacuo. The remaining DMF wasremoved under high vacuum. Crude(1S,2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanol(3.94 g, 8.23 mmol) and 4-(dimethylamino)-pyridine (100 mg, 0.818 mol)were dissolved in pyridine (70.0 mL) and acetic anhydride (4.66 mL, 49.4mmol) was added. The mixture was stirred at rt overnight. The solventwas evaporated and the remaining pyridine was removed under high vacuum.The residue was purified via silica gel chromatography eluting with agradient of 10 to 66% EtOAc in hexanes to afford the title compound(3.66 g, 86%). LC/MS: R_(t)=2.51 min, ES⁺ 521 (AA standard).

Step i:(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentylacetate

(1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentylacetate (3.66 g, 7.03 mmol) was dissolved in THF (31.3 mL) and pyridine(31.3 mL, 387 mmol) in a polypropylene vial and the solution was cooledto 0° C. Pyridine hydrofluoride (8.61 mL, 95.6 mmol) was added dropwiseand the mixture was stirred at rt for 1 hour. The resulting solution wasadded dropwise into a solution of saturated aqueous sodium bicarbonate(150 mL), extracted with EtOAc (3×50 mL), dried with MgSO₄, filtered,and concentrated in vacuo. The residue was purified via silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM to affordthe title compound (2.30 g, 80%). LC/MS: R_(t)=1.64 min, ES⁺ 407 (AAstandard).

Step j:(1S,2S,4R)-2-{[(Aminosulfonyl)oxy]methyl}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentylacetate

A 2.00 M solution of chlorosulfonamide in AcCN was prepared as follows:FA (2.30 mL, 61.0 mmol) was added dropwise, with stirring tochlorosulfonyl isocyanate (5.20 mL, 59.7 mmol) under nitrogen at 0° C.After the addition was complete and the mixture had solidified, AcCN(22.5 mL) was added. The resulting solution was left to stand under avented source of nitrogen overnight at rt.

(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentylacetate (2.30 g, 5.38 mol) was dissolved in AcCN (108 mL) and TEA (3.75mL, 26.9 mmol) was added. The solution was cooled to 0° C. and a 2.00 Msolution of chlorosulfonamide in AcCN (5.38 mL, 10.8 mmol, as preparedabove) was added. The mixture was stirred at rt for 45 min. TLCindicated 50% conversion. Additional 2.00 M chlorosulfonamide in AcCNsolution (5.38 mL, 10.8 mmol) was added and the mixture was stirred atrt for 15 min. At this time, TLC indicated complete conversion. Themixture was quenched with MeOH (3.00 mL), and the solvent was removed invacuo. The residue was purified via silica gel chromatography elutingwith a gradient of 0 to 10% MeOH in EtOAc to afford the title compound(2.45 g, 94%). LC/MS: R_(t)=1.68 min, ES⁺ 486 (AA standard).

Step k:((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-35)

(1S,2S,4R)-2-{[(Aminosulfonyl)oxy]methyl}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentylacetate (2.45 g, 4.54 mmol) was dissolved in a 7.00 M solution ofammonia in MeOH (108 mL) and the mixture was stirred at rt for 5 days.The solvent was removed in vacuo, re-dissolved in DCM and the filteredresidue was purified via silica gel chromatography eluting with agradient of 0 to 10% MeOH in DCM to afford the title compound (1.80 g,90%). ¹H NMR (CD₃OD, 400 MHz, δ): 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.63(d, J=3.6 Hz, 1H), 5.85 (dd, J=7.6, 7.6 Hz, 1H), 5.46-5.40 (m, 1H),4.50-4.47 (m, 1H), 4.37 (d, J=7.6, 9.6 Hz, 1H), 4.19 (dd, J=7.4, 9.6 Hz,1H), 3.08-3.02 (m, 1H), 2.96-2.87 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59(m, 1H), 2.37-2.20 (m, 3H), 2.07-1.97 (m, 2H) ppm. LC/MS: R_(t)=1.54min, ES⁺ 444 (AA standard).

Step l:((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate, Potassium salt

((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (2.64 g, 5.66 mmol) was dissolved in MeOH (43.0 mL) and a1.002 M solution of potassium hydroxide in water (5.64 mL, 5.65 mmol)was added at rt and the mixture was stirred for 1 hour. The solvent wasremoved in vacuo and the solid residue was dried under high vacuum toafford the title compound (2.87 g, 100%). ¹H NMR (CD₃OD, 300 MHz, δ):8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.62 (d, J=3.9 Hz, 1H), 5.85 (dd,J=7.8, 7.8 Hz, 1H), 5.50-5.40 (m, 1H), 4.51-4.48 (m, 1H), 4.22 (dd,J=8.6, 10.0 Hz, 1H), 4.05 (dd, J=6.6, 10.0 Hz, 1H), 3.10-3.00 (m, 1H),2.96-2.85 (m, 1H), 2.81-2.71 (m, 1H), 2.68-2.58 (m, 1H), 2.37-2.13 (m,3H), 2.07-1.94 (m, 2H) ppm. LC/MS: R_(t)=1.54 min, ES⁺ 444 (AAstandard).

Example 2:((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-13) Step a:4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine

To a round bottomed flask with a stir bar was added4-chloro-1H-pyrrolo[2,3-d]-pyrimidine (5.07 g, 33.0 mmol), 1.00 M ofKO-t-Bu in THF (49.5 mL, 49.5 mmol), and benzenemethanethiol (5.81 mL,49.5 mmol) in isopropyl alcohol (350 mL). The reaction mixture washeated to reflux at 85° C. under an atmosphere of nitrogen. After 48 h,the reaction mixture was cooled and solvent was removed in vacuo. To theresidue was added water (300 mL) and the solution was filtered tocollect the resulting white solid. The solid was washed with diethylether and MeOH and dried under vacuum to afford the product as a whitesolid (6.29 g, 79% yield). LC/MS: R_(t)=1.68 min, ES⁺ 242 (FA standard).Reference: Pathak, A. K., Pathak, V., Seitz, L. E., Suling, W. J.,Reynolds, R. C. J. Med. Chem., 2004, 47, 273-276.

Step b:(4aS,6R,7S,7aR)-6-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol

A round-bottomed flask under an atmosphere of argon was charged with4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (194 mg, 0.804 mmol), andDMF (5.00 mL) followed by a 1.00 M solution of lithiumhexamethyldisilazide in THF (0.603 mL, 0.603 mmol). The reaction mixturewas heated to 60° C. After 10 min,(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(100 mg, 0.403 mmol, as prepared in Example 1a-b) in DMF (2.00 mL) wasadded and the reaction was heated to 110° C. After 6 h, the reactionmixture was cooled to rt and saturated aqueous sodium chloride solution(50.0 mL) was added. The aqueous layer was washed with EtOAc (2×50 mL).The combined organic layers were washed with water (2×100 mL), driedover MgSO₄, filtered and concentrated in vacuo. Purification via silicagel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanesafforded the title compound as a white solid (197 mg, 93%). LC/MS:R_(t)=2.07 min, ES⁺ 490. (FA standard).

Step c:O-[(4aS,6R,7S,7aR)-6-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenyl thiocarbonate

To a solution of(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol(990 mg, 2.02 mmol) in DCM (57.0 mL) was added4-(dimethylamino)-pyridine (748 mg, 6.07 mmol) and phenylchlorothionocarbonate (0.565 mL, 4.04 mol) under an atmosphere ofnitrogen and the yellow reaction was stirred at rt. After 12 h, the darkyellow solution was purified via silica gel chromatography eluting with10% EtOAc in hexanes, and then 10% MeOH in DCM on a column pre-treatedwith 1% TEA in hexanes to afford the title compound as a yellow oil(1.77 g, 97%). LC/MS: R_(t)=2.47 min, ES⁺ 626 (FA standard).

Step d:4-(Benzylsulfanyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d]-[1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine

To a solution ofO-[(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenyl thiocarbonate (1.77 g, 1.98 mmol) in toluene (91.0 mL) wasadded 2,2′-azo-bis-isobutyronitrile (67.7 mg, 0.404 mmol) andtri-n-butyltin hydride (1.11 mL, 4.00 mmol) under an atmosphere ofnitrogen. The yellow solution was heated to reflux at 140° C. After 2 h,the reaction mixture was cooled, silica gel was added, and the solventwas removed in vacuo. Silica gel chromatography eluting with a gradientof 0 to 100% EtOAc in hexanes afforded the title compound as asemi-solid (800 mg, 85%). LC/MS: R_(t)=2.38 min, ES⁺ 475 (FA standard).

Step e:4-(Benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d]-[1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine

To a round bottomed flask with a stir bar was added4-(benzylsulfanyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo-[2,3-d]pyrimidine(693 mg, 1.32 mmol) and DCM (32.5 mL). Sodium bicarbonate (400 mg, 4.76mmol) was added followed by 3-chloroperbenzoic acid (754 mg, 3.36 mol)and the reaction mixture was stirred for 12 h. The reaction mixture wasthen treated with saturated aqueous sodium bicarbonate solution,extracted with DCM and the combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatographyeluting with a gradient of 0 to 100% EtOAc in hexanes afforded theproduct as a white solid (219 mg, 32%). LC/MS: R_(t)=1.94 min, ES⁺ 506(FA standard).

Step f:N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In a 0.5-2 mL microwave vial,4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine(100 mg, 0.198 mmol), (R)-(−)-1-aminoindan (0.127 mL, 0.989 mmol), andDIPEA (0.172 mL, 0.989 mol) were dissolved in ethanol (1.22 mL). Thevial was sealed and heated to 110° C. overnight. The solution was thenconcentrated in vacuo and the resulting material was purified via silicagel chromatography eluting with a gradient of 20 to 50% EtOAc in hexanesto afford the product as an orange oil (70.0 mg, 73%). LC/MS: R_(t)=1.42min, ES⁺ 483 (FA standard).

Step g:(1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol

N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(70.0 mg, 0.145 mmol) was added to a solution of AcOH (0.742 mL, 13.0mmol), THF (0.235 mL) and water (0.261 mL). The solution was stirred atrt for 4 days before being concentrated in vacuo. Silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM affordedthe title compound (27.6 mg, 52%). LC/MS: R_(t)=0.94 min, ES⁺ 365 (FAstandard).

Step h: tert-Butyl (chlorosulfonyl)carbamate

To a stirred solution of chlorosulfonyl isocyanate (3.20 mL, 36.0 mmol)in benzene (15.0 mL) in a water bath at rt was added tert-butyl alcohol(3.50 mL, 36.2 mmol) dropwise via syringe under an atmosphere ofnitrogen. After 2 h, the mixture was diluted with hexanes (30.0 mL) andthe resulting white precipitate was filtered and washed with hexanes(3×20 mL). The collected solid was dried in a vacuum desiccator underhouse vacuum for 10 min to afford the title compound as a white solid(5.08 g, 65%). The product was stored under nitrogen in a freezer. ¹HNMR (300 MHz, CDCl₃, δ): 8.44 (br s, 1H), 1.57 (s, 9H) ppm. LC/MS:R_(t)=0.939 min, ES⁺ 215 (AA standard). Reference: F. Hirayama et al.,Biorg. Med. Chem., 2002, 10, 1509-1523.

Step i: tert-Butyl{[((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate

(1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol(27.6 mg, 0.117 mmol) and 2,6-di-tert-butyl-4-methylpyridine (48.5 mg,0.236 mmol) were suspended in AcCN (1.57 mL) and cooled to 0° C.tert-Butyl (chlorosulfonyl)carbamate was added and the mixture wasallowed to warm to rt overnight. The reaction was quenched via additionof MeOH (1.00 mL) and concentrated in vacuo. Silica gel chromatographyeluting with a gradient of 0 to 10% MeOH in DCM afforded the titlecompound (15.2 mg, 37%). LC/MS: R_(t)=1.29 min, ES⁺ 544 (FA standard).

Step j: ((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-13)

tert-Butyl{[((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate(31.0 mg, 0.0570 mmol) was dissolved in DCM (0.803 mL) andtrifluoroacetic acid (0.803 mL, 10.4 mmol) was added. The solution wasstirred at rt for 15 min before being concentrated in vacuo. The residuewas taken up in MeOH (5.00 mL), treated with solid sodium bicarbonate(300 mg) and stirred for 10 min. Filtration and silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM affordedthe title compound (7.20 mg, 58%). ¹H NMR (400 MHz, CD₃OD, 8): 8.17 (s,1H), 7.27-7.14 (m, 5H), 6.64 (d, J=3.5 Hz, 1H), 5.86 (t, J=7.5 Hz, 1H),5.49-5.42 (m, 1H), 4.51-4.48 (m, 1H), 4.38 (dd, J=7.5, 9.8 Hz, 1H), 4.21(dd, J=7.3, 9.8 Hz, 1H), 3.10-3.03 (m, 1H), 2.97-2.88 (m, 1H), 2.86-2.76(m, 1H), 2.68-2.60 (m, 1H), 2.37-2.21 (m, 3H), 2.08-1.97 (m, 2H) ppm.LC/MS: R_(t)=1.16 min, ES⁺ 444 (FA standard).

Example 3:{(1S,2R,3S,4R)-2,3-Dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentyl}methylsulfamate (Compound I-53) Step a:4-(Phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1.69 g, 11.0mmol) and TEA (4.60 mL, 33.0 mmol) in 1-butanol (25.0 mL) was addedbenzenethiol (3.39 mL, 33.0 mmol), and the mixture was refluxed at 140°C. overnight. The reaction was then cooled to rt and concentrated invacuo. The off-white solid was purified by silica gel chromatographyeluting with a gradient of 0 to 35% EtOAc in DCM to afford the product(2.29 g, 92%). LC/MS: R_(t)=1.55 min, ES⁺ 228 (FA standard).

Step b:(4aS,6R,7S,7aR)-2-(4-Methoxyphenyl)-6-[4-(phenylsulfanyl)-1H-pyrrolo[3,2-c]-pyridin-1-yl]hexahydrocyclopenta[d][1,3]dioxin-7-ol

A mixture of 4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (895 mg,3.94 mmol) and NaH (148 mg, 3.69 mmol) in dry DMF (12.0 mL) was stirredat 60° C. for 10 min. Then(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(611 mg, 2.46 mmol) was added and the mixture was heated to 110° C. for5 h. The reaction mixture was then cooled to rt, quenched with saturatedaqueous sodium chloride solution and the solution was extracted twicewith EtOAc. The combined organics were dried over sodium sulfate,filtered and concentrated in vacuo. The crude product mixture waspurified by silica gel chromatography eluting with a gradient of 5 to30% EtOAc in DCM to afford the title compound (96.5 mg, 8.24%). LC/MS:R_(t)=1.95 min, ES⁺ 476 (FA standard).

Step c:(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentane-1,2-diol

To a solution of AcOH (1.04 mL, 18.3 mmol), THF (0.330 mL), and water(0.366 mL) was added(4aS,6R,7S,7aR)-2-(4-methoxyphenyl)-6-[4-(phenylsulfanyl)-1H-pyrrolo[3,2-c]-pyridin-1-yl]hexahydrocyclopenta[d][1,3]dioxin-7-ol(96.7 mg, 0.203 mmol). The reaction solution was stirred at rt for 48 hthen concentrated in vacuo. The resulting oil was purified by silica gelchromatography eluting with a gradient of 60 to 100% EtOAc in hexanes toafford the title compound (32.0 mg, 44%). LC/MS: R_(t)=1.33 min, ES⁺ 358(FA standard).

Step d:{(3aR,4S,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol(320 mg, 0.0895 mmol), 2,2-dimethoxypropane (0.0549 mL, 0.446 mmol), andp-toluenesulfonic acid monohydrate (17.0 mg, 0.0895 mmol) were dissolvedin acetone (2.20 mL) and stirred at rt overnight. Then the reaction wasquenched with saturated sodium bicarbonate solution and approximatelyhalf the solvent was removed in vacuo. The resulting residue was dilutedwith water and extracted with DCM (3×). Combined organics were driedover sodium sulfate, filtered, and concentrated in vacuo to afford thetitle compound as a white foam (35.5 mg, 99%), which was used withoutfurther purification. LC/MS: R_(t)=1.72 min, ES⁺ 389 (FA standard).

Step e:{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methylsulfamate

A solution of{(3aR,4S,6R,6aS)-2,2-dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(35.5 mg, 0.0893 mmol) and pyridine (0.0325 mL, 0.402 mmol) in dry DCM(1.00 mL) was cooled with an ice bath. To this solution was added a 2.00M chlorosulfonamide solution in AcCN (0.178 mL, 0.356 mmol, as preparedin Example 1j) and the reaction was allowed to warm to rt and stirredfor 4 h. The mixture was diluted with DCM, washed with water, andextracted with DCM (3×). Combined organics were dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting oil waspurified by silica gel chromatography eluting with a gradient of 50 to70% EtOAc in hexanes to afford the title compound as a white solid (14.4mg, 34%). LC/MS: R_(t)=1.81 min, ES⁺ 477 (FA standard).

Step f:{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl}methylsulfamate (Compound I-53)

{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methylsulfamate (14.4 mg, 30.2 mmol) was stirred in 1.00 mL of 90%trifluoroacetic acid in water for 3 h at rt. The solvent was thenremoved in vacuo and the resulting oil was purified by silica gelchromatography eluting with a gradient of 60 to 100% EtOAc in hexanes toafford the title compound (7.50 mg, 57%). ¹H NMR (400 MHz, CD₃OD, δ):8.45 (s, 1H), 7.66-7.36 (m, 2H), 7.51-7.41 (m, 4H), 5.92 (d, J=3.8 Hz,1H), 5.13-5.06 (m, 1H), 4.58-4.55 (dd, J=3.8, 9.0 Hz, 1H), 4.42-4.37(dd, J=8.0, 9.8 Hz, 1H), 4.18-4.14 (m, 2H), 2.92-2.82 (m, 1H), 2.24-2.08(m, 2H) ppm. LC/MS: R_(t)=1.38 min, ES⁺ 437 (FA standard).

Example 4:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-7)

The title compound was prepared following the procedure described inExample 1a-k using R-(+)-α-methylbenzylamine in step c. ¹H NMR (400 MHz,CD₃OD, δ): 8.05 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.26 (m, 2H), 7.21-7.16(m, 2H), 6.71 (d, j=3.5 Hz, 1H), 5.46-5.38 (m, 2H), 4.50-4.46 (m, 1H),4.38-4.34 (dd, J=7.5, 9.8 Hz, 1H), 4.21-4.17 (dd, J=7.3, 9.8 Hz, 1H),2.84-2.74 (m, 1H), 2.35-2.15 (m, 3H), 2.06-1.98 (m, 1H), 1.59 (d, J=6.8Hz, 3H) ppm. LC/MS: R_(t)=1.16 min, ES⁺ 432 (FA standard).

Example 5:[(1S,2S,4R)-2-Hydroxy-4-(4-{methyl[(1S)-1-phenylethyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-3)

The title compound was prepared following the procedure described inExample 1a-k using (S)-(−)-N,α-dimethylbenzylamine in step c. ¹H NMR(CD₃OD, 300 MHz, δ): 8.16 (s, 1H), 7.34-7.20 (m, 6H), 6.64 (d, J=3.6 Hz,1H), 6.41-6.34 (m, 1H), 5.54-5.43 (m, 1H), 4.51-4.48 (m, 1H), 4.24 (dd,J=9.6, 9.6 Hz, 1H), 4.07 (dd, J=6.9, 9.6 Hz, 1H), 3.03 (s, 3H),2.80-2.70 (m, 1H), 2.37-2.14 (m, 3H), 2.02-1.88 (m, 1H), 1.64 (d, J=7.2Hz, 3H) ppm. LC/MS: R_(t)=1.64 min, ES⁺ 446 (AA standard).

Example 6:((1S,2S,4R)-4-{4-[(4S)-3,4-Dihydro-2H-chromen-4-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-12)

The title compound was prepared following the procedure described inExample 1a-k using (4S)-chroman-4-amine in step c. ¹H NMR (CD₃OD, 400MHz, δ): 8.28 (s, 1H), 7.43 (d, J=3.6 Hz, 1H), 7.27-7.20 (m, 2H),6.94-6.85 (m, 3H), 5.56-5.48 (m, 1H), 5.34-5.30 (m, 1H), 4.54-4.49 (m,1H), 4.38 (dd, J=7.4, 9.8 Hz, 1H), 4.33-4.29 (m, 2H), 4.21 (dd, J=7.6,9.8 Hz, 1H), 2.90-2.80 (m, 1H), 2.39-2.05 (m, 6H) ppm. LC/MS: R_(t)=1.51min, ES⁺ 460 (AA standard).

Example 7:((1S,2S,4R)-4-{4-[(2,6-Difluorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-15)

The title compound was prepared following the procedure described inExample 1a-k using (2,6-difluorophenyl)methanamine in step c. ¹H NMR(CD₃OD, 300 MHz, δ): 8.17 (s, 1H), 7.39-7.29 (m, 1H), 7.16 (d, J=3.6 Hz,1H), 7.00-6.94 (m, 2H), 6.60 (d, J=3.6 Hz, 1H), 5.48-5.37 (m, 1H), 4.80(s, 2H), 4.50-4.46 (m, 1H), 4.36 (dd, J=7.6, 9.6 Hz, 1H), 4.19 (dd,J=7.2, 9.6 Hz, 1H), 2.85-2.72 (m, 1H), 2.36-2.00 (m, 4H) ppm. LC/MS:R_(t)=1.42 min, ES⁺ 454 (AA standard).

Example 8:{(1S,2S,4R)-4-[4-(Benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (Compound I-49)

The title compound was prepared following the procedure described inExample 1a-k using benzylamine in step c. ¹H NMR (CD₃OD, 400 MHz, δ):8.12 (s, 1H), 7.36-7.20 (m, 6H), 6.62 (d, j=3.6 Hz, 1H), 5.49-5.40 (m,1H), 4.76 (s, 2H), 4.50-4.48 (m, 1H), 4.37 (dd, J=7.6, 10.0 Hz, 1H),4.20 (dd, J=7.6, 10.0 Hz, 1H), 2.85-2.76 (m, 1H), 2.36-2.19 (m, 3H),2.08-2.00 (m, 1H) ppm. LC/MS: R_(t)=1.20 min, ES⁺ 418 (FA standard).

Example 9:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1S)-1-phenylethyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-4)

The title compound was prepared following the procedure described inExample 1a-k using (1S)-(−)-α-methylbenzylamine in step c. ¹H NMR (400MHz, CD₃OD, δ): 8.05 (s, 1H), 7.41-7.39 (d, J=7.6 Hz, 2H), 7.31-7.27 (m,2H), 7.22-7.17 (m, 2H), 6.72 (d, J=3.3 Hz, 1H), 5.46-5.38 (m, 2H),4.48-4.47 (br s, 1H), 4.37 (dd, J=7.6, 9.6 Hz, 1H), 4.21-4.17 (m, 1H),2.84-2.75 (m, 1H), 2.37-2.18 (m, 3H), 2.07-1.94 (m, 1H), 1.61-1.59 (d,J=7.0 Hz, 3H) ppm. LC/MS: R_(t)=1.50 min, ES⁺ 432 (AA standard).

Example 10:((1S,2S,4R)-4-{4-[Benzyl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-10)

The title compound was prepared following the procedure described inExample 2a-j using N-methylbenzylamine in step f. ¹H NMR (400 MHz,DMSO-d6, δ): 8.24 (s, 1H), 7.44-7.25 (m, 5H), 7.31-7.23 (m, 3H), 6.64(br s, 1H), 5.49-5.37 (m, 1H), 5.04 (s, 2H), 4.37-4.30 (m, 1H), 4.23(dd, J=7.0, 9.7 Hz, 1H), 4.04 (dd, J=8.0, 9.6 Hz, 1H), 3.35 (s, 3H),2.77-2.64 (m, 1H), 2.22-1.87 (m, 4H) ppm. LC/MS: R_(t)=1.51 min, ES⁺ 432(AA standard).

Example 11:((1S,2S,4R)-4-{4-[(2-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-1)

The title compound was prepared following the procedure described inExample 2a-j using 2-chlorobenzylamine in step f. ¹H NMR (400 MHz,DMSO-d6, δ): 8.10 (s, 1H), 8.03-7.94 (m, 1H), 7.48-7.42 (m, 1H), 7.38(s, 1H), 7.36-7.24 (m, 4H), 6.65 (d, J=3.2 Hz, 1H), 5.36 (dt, J=8.9,14.2 Hz, 1H), 4.89 (d, J=3.9 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.36-4.30(m, 1H), 4.24 (dd, J=7.0, 9.7 Hz, 1H), 4.05 (dd, J=8.1, 9.5 Hz, 1H),2.77-2.66 (m, 1H), 2.24-2.02 (m, 3H), 1.99-1.89 (m, 1H) ppm. LC/MS:R_(t)=1.51 min, ES⁺ 452 (AA standard).

Example 12:{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methylsulfamate and((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compounds I-40 and I-6) Step a: tert-Butyl(1S)-2,3-dihydro-1H-inden-1-ylcarbamate

To a solution of (S)-(+)-1-aminoindan (1.24 g, 9.22 mmol) in THF (20.0mL) was added TEA (1.42 mL, 10.1 mmol) followed bydi-tert-butyldicarbonate (2.07 g, 9.22 mmol) and the mixture was stirredunder an atmosphere of nitrogen for 24 h. The mixture was concentratedin vacuo and purified via silica gel chromatography eluting with agradient of 0 to 20% EtOAc in hexanes to afford the title compound as awhite solid (2.02 g, 94%). LC/MS: R_(t)=1.94 min, ES⁺ 234 (AA standard).

Step b: tert-Butyl (1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of tert-butyl (1S)-2,3-dihydro-1H-inden-1-ylcarbamate(1.82 g, 7.80 mmol) in THF (50.0 mL) under an atmosphere of argon at 0°C. was added 60% sodium hydride in mineral oil (968 mg, 24.2 mmol) andthe suspension was allowed to warm to rt and stir for 30 min.Iodomethane (1.52 mL, 24.2 mmol) was added and the mixture was stirredovernight. The reaction was then quenched via addition of saturatedammonium chloride solution (10.0 mL) and was concentrated in vacuo. Themixture was then partitioned between water (20 mL) and DCM (50 mL) andthe aqueous layer was extracted with DCM (3×50 mL). The combined organiclayers were dried over MgSO₄, filtered, concentrated in vacuo andpurified by silica gel chromatography eluting with a gradient of 0 to20% EtOAc in hexanes to afford the title compound as a clear, colorlessoil (1.84 g, 95%). LC/MS: R_(t)=2.21 min, ES⁺ 248 (AA standard).

Step c: (1S)-N-Methylindan-1-amine, hydrochloride salt

To a solution of tert-butyl(1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate (1.84 g, 7.44 mmol) inMeOH (50.0 mL) under an atmosphere of nitrogen was added hydrochloricacid (6.00 mL, 72.4 mmol) and the mixture was stirred overnight. Thereaction was concentrated in vacuo to afford the title compound as awhite solid without further purification (1.35 g, 99%). LC/MS:R_(t)=0.85 min, ES⁺ 148 (AA standard).

Step d: tert-Butyl{[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate

The title compound was prepared following the procedure described inExample 2a-i using (1S)-N-methylindan-1-amine, hydrochloride salt instep f. LC/MS: R_(t)=1.55 min, ES⁺ 558 (AA standard).

Step e:{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methylsulfamate and((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compounds I-40 and I-6)

To a solution of tert-butyl{[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]-sulfonyl}carbamate(97.9 mg, 0.176 mmol) in DCM (5.00 mL) under an atmosphere of nitrogenwas added trifluoroacetic acid (5.00 mL, 64.9 mmol). LC/MS after 10 minindicated the presence of both products, and the mixture wasconcentrated in vacuo and purified via silica gel chromatography elutingwith a gradient of 0 to 10% MeOH in EtOAc to afford both products asclear, colorless oils (9.70 mg, 10% and 30.6 mg, 51%, respectively).Analytical data for{(1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methylsulfamate (Compound I-40): ¹H NMR (400 MHz, CD₃OD, δ): 8.18 (s, 1H),7.38 (d, J=3.6 Hz, 1H), 6.74 (d, j=3.1 Hz, 1H), 5.53-5.42 (m, 1H),4.51-4.47 (m, 1H), 4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.4, 9.7Hz, 1H), 3.34 (s, 3H), 3.14 (br s, 3H), 2.90-2.75 (m, 1H), 2.37-2.18 (m,3H), 2.12-1.96 (m, 1H) ppm. LC/MS: R_(t)=1.03 min, ES⁺ 342 (AAstandard). Analytical data for((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-6): ¹H NMR (400 MHz, CD₃OD, δ): 8.28 (s, 1H), 7.54(d, J=3.8 Hz, 1H), 7.39-7.21 (m, 4H), 7.02 (d, J=3.8 Hz, 1H), 6.26 (dd,J=7.5, 7.5 Hz, 1H), 5.58 (ddd, J=5.2, 8.9, 17.9 Hz, 1H), 5.47 (s, 1H),4.51 (dd, J=3.3, 3.3 Hz, 1H), 4.38 (dd, J=7.4, 9.8 Hz, 1H), 4.20 (dd,J=7.5, 9.7 Hz, 1H), 3.23-2.96 (m, 6H), 2.93-2.79 (m, 1H), 2.76-2.59 (m,1H), 2.42-2.05 (m, 6H) ppm. LC/MS: R_(t)=1.89 min, ES⁺ 458 (AAstandard).

Example 13:{(1S,2S,4R)-4-[4-(Benzylamino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (Compound I-31) Step a:4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (3.00 g,19.5 mmol) in AcCN (148 mL) was added Selectfluor™(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-octanebis(tetrafluoroborate)), 10.4 g, 29.4 mmol) and AcOH (29.8 mL, 524mmol), and then the mixture was allowed to stir for 26 hrs at 70° C.under an atmosphere of nitrogen. After cooling to rt, the mixture wasconcentrated in vacuo and the mixture was co-evaporated with dry toluene(2×30 mL). The residue was dissolved in a solution of 50% DCM in EtOAcand filtered through a pad of silica gel which was thoroughly washed.The filtrate was concentrated in vacuo, the residue was purified bysilica gel chromatography eluting with a gradient of 0 to 30% EtOAc inDCM to afford the title compound as a light brown solid (1.22 g, 36%).LC/MS: R_(t)=1.51 min, ES⁺ 243 (AA standard).

Step b: {[(1S,2S,4R)-4-[4-(Benzylamino)-5-fluoro-7H-pyrrolo2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methyl sulfamate (CompoundI-31)

The title compound was prepared following the procedure described inExample 1a-k using benzylamine and4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine in step c. ¹H NMR (400MHz, CD₃OD, δ): 8.09 (s, 1H), 7.37-7.32 (m, 2H), 7.31-7.26 (m, 2H),7.23-7.19 (m, 1H), 7.06 (d, J=2.0 Hz, 1H), 5.50-5.42 (m, 1H), 4.76 (brs, 2H), 4.47-4.43 (m, 1H), 4.34 (dd, J=7.8, 9.8 Hz, 1H), 4.17 (dd,J=7.2, 9.8 Hz, 1H), 2.81-2.72 (m, 1H), 2.29 (ddd, J=1.5, 8.0 Hz, 14.0Hz, 1H), 2.25-2.13 (m, 2H), 1.98 (ddd, J=5.0, 9.4, 14.0 Hz, 1H). LC/MS:R_(t)=1.56 min, ES⁺ 436 (AA standard).

Example 14:((1S,2S,4R)-4-{4-[(Cyclohexylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-29)

The title compound was prepared following the procedure described inExample 1a-k using cyclohexanemethylamine in step c. ¹H NMR (300 MHz,CD₃OD, δ): 8.08 (s, 1H), 7.17 (d, J=3.6 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H),5.47-5.35 (m, 1H), 4.50-4.46 (m, 1H), 4.36 (dd, J=7.6, 9.8 Hz, 1H), 4.19(dd, J=7.3, 9.8 Hz, 1H), 3.35 (br s, 1H), 3.34 (br s, 2H), 3.32 (br s,1H), 2.85-2.72 (m, 1H), 2.36-2.15 (m, 3H), 2.01 (ddd, J=4.9, 9.2, 14.3Hz, 1H), 1.88-1.60 (m, 6H), 1.36-1.15 (m, 3H), 1.06-0.91 (m, 2H). LC/MS:R_(t)=1.60 min, ES⁺ 424 (AA standard).

Example 15:((1S,2R,3S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-17) Step a:(1R,2S,3R,5S)-3-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol

To a solution of(4aS,6R,7R,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)-7-methylhexahydrocyclopenta[d][1,3]-dioxin-7-ol(312 mg, 0.594 mmol, as prepared following the procedure in Example1a-d, using (S)-(+)-1-aminoindan in step c) in THF (1.17 mL) and water(1.17 mL) was added AcOH (3.51 mL, 61.7 mmol) under an atmosphere ofnitrogen. The mixture was stirred at rt overnight. The solvent wasremoved in vacuo and the residue was purified by silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM to affordthe title compound as a white solid (182 mg, 76%). LC/MS: R_(t)=0.85min, ES⁺ 381 (FA standard).

Step b:((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

To a suspension of(1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol(63.8 mg, 0.168 mmol) and 2,2-dimethoxypropane (0.103 mL, 0.838 mmol) inacetone (2.10 mL) was added p-toluenesulfonic acid monohydrate (31.9 mg,0.168 mmol) with rapid stirring. The resulting solution was stirredovernight. The reaction was quenched with saturated aqueous sodiumbicarbonate solution (1.00 mL) and the volume was reduced in vacuo. Thesolution was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with saturated aqueous sodium chloridesolution, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography eluting with agradient of 10 to 60% EtOAc in hexanes to afford the title compound as awhite solid (49.6 mg, 70.%). LC/MS: R_(t)=1.16 min, ES⁺ 421 (FAstandard).

Step c:((1S,2R,3S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]l-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-17)

To a suspension of((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(45.9 mg, 0.109 mmol) and pyridine (0.0180 mL, 0.222 mmol) in AcCN (1.10mL) and DCM (0.500 mL) at 0° C. under an atmosphere of nitrogen wasadded dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.110 mL,0.220 mmol, as prepared in 1j). The suspension was stirred for 2 h andmore 2.00 M of chlorosulfonamide in AcCN solution (0.150 mL, 3.00 mmol)was added. After 5 min the reaction was quenched with MeOH (1.00 mL) andthe solvent was removed in vacuo. The residue was purified by silica gelchromatography eluting with a gradient of 0 to 10% MeOH in DCM to affordthe title compound as a white solid (23.1 mg, 46%). ¹H NMR (400 MHz,CD₃OD, δ): 8.36 (s, 1H), 7.62 (d, J=3.1 Hz, 1H), 7.43-7.33 (m, 4H), 7.04(d, J=3.0 Hz, 1H), 5.67 (br s, 1H), 5.25-5.20 (m, 1H), 4.61 (dd, J=3.8,9.3 Hz, 1H), 4.48 (dd, J=2.0, 9.9 Hz, 1H), 4.27-4.22 (m, 2H), 3.74 (s,1H), 3.27-3.20 (m, 1H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.77(m, 1H), 2.35-2.19 (m, 3H) ppm. LC/MS: R_(t)=0.94 min, ES⁺ 460. (FAstandard).

Example 16:((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methylsulfamate and((1S,3S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclopentyl)methylsulfamate (Compounds I-20 and I-11) Step a:(1S,2R,3S,5R)-3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol

A solution of(1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol(166 mg, 0.436 mmol, as prepared in Example 15a),tert-butyldimethylsilyl chloride (69.0 mg, 0.458 mmol), 1H-imidazole(44.6 mg, 0.654 mmol) in DMF (2.00 mL) was stirred under an atmosphereof nitrogen. After 2 h additional tert-butyldimethylsilyl chloride (6.00mg, 0.0365 mmol) was added and the solution was stirred for 1 hour. Thereaction was quenched with water and extracted with EtOAc. The combinedorganics were washed with water and saturated aqueous sodium chloridesolution, dried over sodium sulfate, filtered, and concentrated invacuo. The residue filtered through a plug of silica gel eluting with60% EtOAc in hexanes to afford the title compound as an off white solid(179 mg, 83%). LC/MS: R_(t)=1.51 min, ES⁺ 495 (FA standard).

Step b:(3aR,4S,6R,6aS)-4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydro-3aH-cyclopenta[d][1,3]dioxole-2-thione

To a solution of(1S,2R,3S,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol(179 mg, 0.362 mmol) in DMF (2.00 mL) under an atmosphere of nitrogenwas added 1,1′-thiocarbonyldiimidazole (72.3 mg, 0.406 mmol) and thesolution was heated to 80° C. for 3 h. The solvent was removed and theresidue was purified by silica gel chromatography eluting with agradient of 0 to 50% EtOAc in hexanes to afford the title compound (158mg, 81%). LC/MS: R_(t)=2.24 min, ES⁺ 538 (FA standard).

Step c:7-[(1R,4R)-4-({[tert-Butyl(dimethyl)siyl]oxy}methyl)cyclopent-2-en-1-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of(3aR,4S,6R,6aS)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydro-3aH-cyclopenta[d][1,3]dioxole-2-thione(138 mg, 0.257 mmol) in THF (0.860 mL) at 0° C. under an atmosphere ofnitrogen was added 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.147mL, 0.793 mmol) dropwise. The solution was stirred for 10 min at 0° C.and then at rt for 5 h. The solvent was removed and the residue waspurified by silica gel chromatography eluting with a gradient of 0 to20% EtOAc in hexanes to afford the title compound as a clear oil (˜70%purity, 81.9 mg, 48%). LC/MS: R_(t)=2.10 min, ES⁺ 462 (FA standard).

Step d:((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methanol

To a solution of7-[(1R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(81.9 mg, 0.178 mmol) in pyridine (0.800 mL) and THF (0.800 mL) at 0° C.under an atmosphere of nitrogen was added dropwise pyridinehydrofluoride (0.0500 mL, 0.555 mol). The solution was warmed to rt andstirred overnight. The reaction was quenched with saturated aqueoussodium bicarbonate solution and diluted with EtOAc. The layers wereseparated and the aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography eluting with a gradient of 0 to 5% MeOH in DCM to affordthe title compound as a white solid (˜70% purity, 35.7 mg, 41%). LC/MS:R_(t)=1.03 min, ES⁺ 347 (FA standard).

Step e:((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopent-2-en-1-yl)methylsulfamate (Compound I-20)

To a solution of((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}cyclopent-2-en-1-yl)methanol(35.7 mg, 0.103 mmol) and pyridine (0.0417 mL, 0.515 mmol) in AcCN (1.00mL) at 0° C. under an atmosphere of nitrogen was added dropwise a 2.00 Msolution of chlorosulfonamide in AcCN (0.260 mL, 0.520 mmol, as preparedin 1j). The solution was stirred for 1 hour. The reaction was quenchedwith saturated aqueous sodium bicarbonate solution and partitionedbetween water and EtOAc. The layers were separated and the aqueous layerwas extracted with EtOAc (2×20 mL). The combined organic layers werewashed with saturated aqueous sodium chloride solution, dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography eluting with a gradient of 0 to 5%MeOH in DCM to afford the title compound as a solid (28.9 mg, 66%). ¹HNMR (400 MHz, CDCl₃, δ): 8.36 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.30-7.18(m, 3H), 6.89 (d, J=3.6 Hz, 1H), 6.32 (d, J=3.5 Hz, 1H), 6.14-6.12 (m,1H), 6.04-5.97 (m, 2H), 5.89 (br s, 1H), 4.19 (dd, J=1.2, 6.0 Hz, 2H),3.43-3.37 (m, 1H), 3.09-3.01 (m, 1H), 2.98-2.90 (m, 1H), 2.77-2.69 (m,1H), 2.46-2.39 (m, 1H), 2.07-1.93 (m, 3H) ppm. LC/MS: R_(t)=1.24 min,ES⁺ 426 (FA standard).

Step f:((1S,3S)-3-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamate (Compound I-11)

A suspension of((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}cyclopent-2-en-1-yl)methylsulfamate (17.3 mg, 0.0406 mmol) and 10% palladium on carbon (8.60 mg)in EtOAc (0.500 mL) was put under an atmosphere of hydrogen. After 3 hthe flask was purged with nitrogen and the suspension was filteredthrough Celite eluting with EtOAc to afford the title compound as awhite solid (10.8 mg, 62%). ¹H NMR (400 MHz, CDCl₃, δ): 8.36 (s, 1H),7.36 (d, J=7.3 Hz, 1H), 7.29-7.15 (m, 3H), 7.00 (d, J=3.4 Hz, 1H), 6.33(d, J=3.4 Hz, 1H), 5.91-5.87 (m, 1H), 5.41 (br s, 2H), 5.23-5.15 (m,2H), 4.26 (dd, J=5.8, 9.8 Hz, 1H), 4.18 (dd, J=6.2, 9.8 Hz, 1H),3.09-3.02 (m, 1H), 2.99-2.90 (m, 1H), 2.36-2.27 (m, 2H), 2.21-2.12 (m,2H), 2.09-1.93 (m, 3H), 1.66-1.57 (m, 1H) ppm. LC/MS: R_(t)=1.24 min,ES⁺ 428 (FA standard).

Example 17:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-1H-pyrrolo[2,3-d]pyridazin-1-yl)cyclopentyl]methylsulfamate (Compound I-41) Step a:N-[(5-Methylisoxazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (1.14 g, 7.43 mmol),(5-methyl-3-isoxazolyl)methylamine (1.00 g, 8.92 mmol) and DIPEA (1.94mL, 11.1 mmol) were added to 1-butanol (9.13 mL). The mixture was heatedat 190° C. for 1600 seconds using MWI in three batches. The combinedreactions were concentrated in vacuo to give a brown oil. The residuewas purified by silica gel chromatography eluting with EtOAc to affordthe title compound as a yellow solid (1.22 g, 72%). LC/MS: R_(t)=0.63min, ES⁺ 230. (FA standard).

Step b:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-1H-pyrrolo-[2,3-d]pyridazin-1-yl)cyclopentyl]methylsulfamate (Compound I-41)

The title compound was prepared following the procedure described inExample Id-k usingN-[(5-methylisoxazol-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine instep d. ¹H NMR (400 MHz, CD₃OD, δ): 8.22 (s, 1H), 7.26 (d, J=3.6 Hz,1H), 6.63 (d, J=3.6 Hz, 1H), 6.14 (s, 1H), 5.55-5.44 (m, 1H), 4.81 (s,2H), 4.59 (br s, 1H), 4.42 (dd, J=7.6, 9.6 Hz, 1H), 4.25 (dd, J=7.4, 9.8Hz, 1H), 2.91-2.79 (m, 1H), 2.41 (s, 3H), 2.40-2.22 (m, 3H), 2.15-2.04(m, 1H) ppm.

LC/MS: R_(t)=0.89 min, ES⁺ 423 (FA standard).

Example 18:[(1S,2S,4R)-4-(4-Anilino-1H-pyrrolo[2,3-d]pyridazin-1-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-39)

The title compound was prepared following the procedure described inExample 17a-b using aniline in step a. ¹H NMR (400 MHz, CD₃OD, δ): 8.18(s, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.31 (dd, J=7.5, 8.4 Hz, 2H), 7.23 (d,J=3.7 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.22 (d, J=3.7 Hz, 1H), 5.50-5.39(m, 1H), 4.46 (br s, 1H), 4.34 (dd, J=7.6, 7.6 Hz, 1H), 4.16 (dd, J=7.4,7.4 Hz, 1H), 2.89-2.73 (m, 1H), 2.37-2.15 (m, 3H), 2.09-1.97 (m, 1H)ppm. LC/MS: R_(t)=1.03 min, ES⁺ 404 (FA standard).

Example 19:[(1S,2S,4R)-2-Hydroxy-4-(4-{[2-(trifluoromethyl)benzyl]amino}-1H-pyrrolo-[2,3-d]pyridazin-1-yl)cyclopentyl]methylsulfamate (Compound I-47)

The title compound was prepared following the procedure described inExample 17a-b using 2-(trifluoromethyl)benzylamine in step a. ¹H NMR(400 MHz, CD₃OD, δ): 8.08 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.47 (d,J=4.0 Hz, 2H), 7.42-7.34 (m, 1H), 7.19 (d, J=3.7 Hz, 1H), 6.60 (d, J=3.2Hz, 1H), 5.50-5.36 (m, 1H), 4.94 (s, 1H), 4.45 (br s, 1H), 4.34 (dd,J=7.5, 7.6 Hz, 1H), 4.16 (dd, J=7.4, 7.4 Hz, 1H), 3.27 (q, J=1.6, 3.3Hz, 1H), 2.94-2.73 (m, 1H), 2.35-2.15 (m, 3H), 2.06-1.96 (m, 1H) ppm.LC/MS: R_(t)=1.25 min, ES⁺ 486 (FA standard).

Example 20:((1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-25) Step a:(1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol

The title compound was prepared following the procedure described inExample 1a-g using cyclopropylmethylamine in step c. LC/MS: R_(t)=0.90min, ES⁺ 303 (FA standard).

Step b:7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol(280 mg, 0.923 mmol) was stirred in DMF (3.00 mL).tert-Butyldimethylsilyl chloride (698 mg, 4.63 mmol) was added followedby 1H-imidazole (142 mg, 2.08 mmol) and 4-(dimethylamino)-pyridine (10.0mg, 0.0818 mmol). The reaction was stirred for 1 h then diluted withwater and extracted with EtOAc (3×15 mL). The organic layer was driedover MgSO₄, filtered and concentrated in vacuo. The resulting oil wasdried under high vacuum overnight. The residue was purified by silicagel chromatography eluting with a gradient of 0 to 15% EtOAc in hexanesto afford the title compound (203 mg, 41%). LC/MS: R_(t)=2.16 min, ES⁺531 (FA standard).

Step c:((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol

7-[(1R,3S,4S)-3-{([tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(100 mg, 0.188 mmol) was dissolved in THF (0.900 mL) and pyridine (0.900mL). Pyridine hydrofluoride (7 drops) was added and the reaction wasstirred for 5 h. Additional pyridine hydrofluoride (3 drops) was addedand the reaction was stirred for 2 h before being quenched withsaturated aqueous sodium bicarbonate solution. The aqueous layer wasextracted using EtOAc (3×10 mL), and the combined organic extracts weredried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography eluting with a gradient of 0 to50% EtOAc in hexanes to afford the title compound (47.0 mg, 50%). LC/MS:R_(t)=1.53 min, ES⁺ 417 (FA standard).

Step d:((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamate

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol(74.0 mg, 0.178 mmol) was dissolved in AcCN (3.50 mL) and cooled to 0°C. TEA (0.0500 mL, 0.355 mmol) was added followed by a 2.00 M solutionof chlorosulfonamide in AcCN (0.178 mL, 0.356 mmol, as prepared in 1j).The reaction was stirred for 2 h, quenched with MeOH and concentrated invacuo. The material was taken on to the next step without furtherpurification. LC/MS: R_(t)=1.51 min, ES⁺ 496 (FA standard).

Step e:((1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-25)

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamate (88.0 mg, 0.178 mmol) was dissolved in THF (1.00 mL) andpyridine (3.00 mL). Pyridine hydrofluoride (12 drops) was added and thereaction was stirred for 3 h. The reaction was quenched using saturatedaqueous sodium bicarbonate solution. The aqueous layer was extractedwith EtOAc (3×10 mL), and the combined organic extracts were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography eluting with 5% MeOH in DCM. The compound wasre-purified via silica gel chromatography eluting with 10% MeOH in DCMto afford the title compound (3.00 mg, 4.4%). ¹H NMR (400 MHz, CD₃OD,δ): 8.05 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.6 Hz, 1H),5.45-5.32 (m, 1H), 4.56 (br s, 1H), 4.45 (br s, 1H), 4.33 (dd, J=7.6,7.6 Hz, 1H), 4.15 (dd, J=7.4, 7.4 Hz, 1H), 3.34 (d, J=6.9 Hz, 2H),2.83-2.68 (m, 1H), 2.35-2.08 (m, 3H), 2.05-1.93 (m, 1H), 1.33-1.03 (m,3H), 0.93-0.77 (m, 1H) ppm. LC/MS: R_(t)=0.85 min, ES⁺ 382 (FAstandard).

Example 21:((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-34)

Step a: 4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidine

To a 0.375 M solution of aqueous potassium hydroxide (26.2 mL, 9.83mmol) was added (4-chlorophenyl)methanol (464 mg, 3.26 mmol) and themixture was heated to 80° C. for 30 min. Then4-chloro-1H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol) was added andthe mixture was refluxed at 130° C. After 6 h, additional(4-chlorophenyl)methanol (100 g, 0.701 mmol) was added and the solutionwas heated to 115° C. overnight. The reaction was cooled to rt anddiluted with water. The solution was then extracted with EtOAc (2×) andDCM (2×). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. The resulting crude oil waspurified by silica gel chromatography eluting with a gradient of 5 to30% EtOAc in DCM to afford the product as a white solid (210 mg, 25%).LC/MS: R_(t)=1.72 min, ES⁺ 260. (FA standard).

Step b:((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-34)

The title compound was prepared following the procedure described inExample 1d-g and then Example 2i-j, using4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-d]pyrimidine in step 1d. ¹H NMR(400 MHz, CD₃OD, δ): 8.35 (s, 1H), 7.51-7.34 (m, 5H), 6.56 (d, J=3.5 Hz,1H), 5.55 (s, 2H), 5.54-5.46 (m, 1H), 4.52-4.48 (m, 1H), 4.37 (dd,J=7.8, 10.0 Hz, 1H), 4.20 (dd, J=7.3, 9.8 Hz, 1H), 2.90-2.80 (m, 1H),2.34-2.20 (m, 3H), 2.11-2.03 (m, 1H) ppm. LC/MS: R_(t)=1.81 min, ES⁺ 453(FA standard).

Example 22:{(1S,2S,4R)-4-[4-(Benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (Compound I-32)

The title compound was prepared following the procedure described inExample 2a-d and g-j. ¹H NMR (400 MHz, CD₃OD, δ): 8.54 (s, 1H),7.45-7.36 (m, 3H), 7.28-7.14 (m, 3H), 6.47 (d, J=3.6 Hz, 1H), 5.51-5.43(m, 1H), 4.58 (s, 2H), 4.49-4.45 (m, 1H), 4.33 (dd, J=7.6, 9.7 Hz, 1H),4.16 (dd, J=7.3, 9.7 Hz, 1H), 2.87-2.78 (m, 1H), 2.62 (s, 2H), 2.32-2.15(m, 3H), 2.08-2.01 (m, 1H) ppm. LC/MS: R_(t)=1.97 min, ES⁺ 435 (FAstandard).

Example 23:((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-45)

The title compound was prepared following the procedure described inExample 2a-j using 4-chlorobenzylamine in step f. ¹H NMR (400 MHz,CD₃OD, δ): 8.10 (s, 1H), 7.34-7.28 (m, 4H), 7.21 (d, J=3.6 Hz, 1H), 6.59(d, J=3.6 Hz, 1H), 5.47-5.39 (m, 1H), 4.73 (s, 2H), 4.50-4.48 (m, 1H),4.25 (dd, J=8.3, 9.9 Hz, 1H), 4.09 (dd, J=6.8, 10.0 Hz, 1H), 3.35-3.33(m, 2H), 2.81-2.71 (m, 1H), 2.35-2.29 (m, 1H), 2.26-2.15 (m, 2H),2.02-1.96 (m, 1H) ppm. LC/MS: R_(t)=5.39 min, ES⁺ 452 (FA standard, longpurity method)

Example 24:((1S,2S,4R)-4-{4-[(3-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-51)

The title compound was prepared following the procedure described inExample 2a-j using 3-chlorobenzylamine in step f. ¹H NMR (400 MHz,CD₃OD, δ): 8.22 (s, 1H), 7.44-7.31 (m, 5H), 6.78 (d, J=3.6 Hz, 1H),5.56-5.48 (m, 1H), 4.82 (s, 2H), 4.56-4.52 (m, 1H), 4.42 (dd, J=7.5, 9.8Hz, 1H), 4.25 (dd, J=7.3, 9.8 Hz, 1H), 2.92-2.83 (m, 1H), 2.42-2.26 (m,3H), 2.15-2.08 (m, 1H) ppm. LC/MS: R_(t)=1.51 min, ES⁺ 452 (FAstandard).

Example 25:((1S,2S,4R)-4-{4-[(4-Chloro-2-methylbenzyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-48)

The title compound was prepared following the procedure described inExample 2a-j using 4-chloro-2-methylbenzylamine in step f. ¹H NMR (400MHz, CD₃OD, δ): 8.12 (s, 1H), 7.26-7.21 (m, 3H), 7.14-7.11 (m, 1H), 6.66(d, J=3.5 Hz, 1H), 5.49-5.41 (m, 1H), 4.69 (s, 2H), 4.50-4.47 (m, 1H),4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.5, 9.8 Hz, 1H), 2.86-2.76(m, 1H), 2.36 (s, 3H), 2.33-2.19 (m, 3H), 2.08-2.01 (m, 1H) ppm. LC/MS:R_(t)=1.11 min, ES⁺ 466 (FA standard).

Example 26:((1S,2S,4R)-2-Hydroxy-4-{4-[(2-methoxybenzyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopentyl)methylsulfamate (Compound I-43)

The title compound was prepared following the procedure described inExample 2a-j using 2-methoxybenzylamine in step f. ¹H NMR (400 MHz,CD₃OD, δ): 8.08 (s, 1H), 7.24-7.18 (m, 3H), 6.96 (d, J=7.8 Hz, 1H), 6.85(dt, J=0.8, 7.3 Hz, 1H), 6.61 (d, J=3.5 Hz, 1H), 5.47-5.39 (m, 1H), 4.72(s, 2H), 4.50-4.46 (m, 1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd,J=7.3, 9.8 Hz, 1H), 3.87 (s, 3H), 2.84-2.75 (m, 1H), 2.35-2.18 (m, 3H),2.06-1.99 (m, 1H) ppm. LC/MS: R_(t)=1.16 min, ES⁺ 448 (FA standard).

Example 27:((1S,2S,4R)-4-{4-[(3,4-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-24)

The title compound was prepared following the procedure described inExample 2a-j using 3,4-dichlorobenzylamine in step f. ¹H NMR (400 MHz,CD₃OD, δ): 8.15 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H),7.30-7.27 (m, 2H), 6.65 (d, J=3.5 Hz, 1H), 5.48-5.41 (m, 1H), 4.74 (s,2H), 4.49 (t, J=4.0 Hz, 1H), 4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.20 (dd,J=7.5, 9.8 Hz, 1H), 2.86-2.77 (m, 1H), 2.36-2.20 (m, 3H), 2.08-2.01 (m,1H) ppm. LC/MS: R_(t)=1.16 min, ES⁺ 486 (FA standard).

Example 28:((1S,2S,4R)-2-Hydroxy-4-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamate (Compound I-37)

The title compound was prepared following the procedure described inExample 2a-j using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine in step f.¹H NMR (400 MHz, CD₃OD, δ): 8.16 (s, 1H), 7.26-7.07 (m, 5H), 6.63 (d,J=3.5 Hz, 1H), 5.56-5.50 (m, 1H), 5.49-5.41 (m, 1H), 4.50 (m, 1H), 4.38(dd, J=7.5, 9.8 Hz, 1H), 4.20 (dd, J=7.3, 9.8 Hz, 1H), 2.93-2.76 (m,3H), 2.37-2.20 (m, 3H), 2.17-1.82 (m, 5H) ppm. LC/MS: R_(t)=1.29 min,ES⁺ 458 (FA standard).

Example 29:((1S,2R,3S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-22)

The title compound was prepared following the procedure described inExample 2a-d and g-j using 4-chlorobenzylamine in step f. ¹H NMR (300MHz, CD₃OD, δ): 8.11 (s, 1H), 7.34-7.21 (m, 5H), 6.60 (d, J=3.6 Hz, 1H),5.06-4.97 (m, 1H), 4.74 (s, 2H), 4.51 (dd, J=3.6, 9.2 Hz, 1H), 4.40 (dd,J=8.0, 9.6 Hz, 1H), 4.18-4.14 (m, 2H), 2.88-2.78 (m, 1H), 2.23-2.02 (m,2H) ppm. LC/MS: R_(t)=1.46 min, ES⁺ 468 (AA standard).

Example 30:((1S,2S,4R)-4-{6-[(4-Chlorobenzyl)amino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-23)

The title compound was prepared following the procedure described inExample 1a-f and Example 2h-j, using 4-chlorobenzylamine and6-chloro-9H-purine in step 1c. ¹H NMR (300 MHz, CD₃OD, δ): 8.23 (s, 1H),8.14 (s, 1H), 7.35-7.25 (m, 4H), 5.31-5.22 (m, 1H), 4.79 (s, 2H),4.51-4.49 (br s, 1H), 4.37 (dd, J=7.5, 9.6 Hz, 1H), 4.23-4.17 (m, 1H),2.93-2.87 (m, 1H), 2.47-2.30 (m, 2H), 2.28-2.10 (m, 2H) ppm. LC/MS:R_(t)=1.42 min, ES⁺ 453 (AA standard).

Example 31:[(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-46) Step a: 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine

A 3.00 M solution of magnesium chloride in THF (13.0 mL, 39.0 mmol) wasadded dropwise to a stirred solution of4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.50 g, 16.3 mmol) and ferricacetylacetonate (700 mg 1.98 mmol) in THF (30.0 mL) under an atmosphereof argon. The resulting reaction mixture was stirred at rt for 8 h. Themixture was poured onto a mixture of ice (100 mL) and ammonium chloride(1.00 g) and the mixture was extracted with chloroform. Volatiles wereremoved in vacuo, and C-18 column chromatography eluting with a gradientof 0 to 60% AcCN in water with 0.1% AA afforded the title compound (1.50g, 69%). LC/MS: R_(t)=0.94 min, ES⁺ 134 (AA standard).

Step b:[(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]-methylsulfamate (Compound I-46)

The title compound was prepared following the procedure described inExample 1a-k using 4-methyl-7H-pyrrolo[2,3-d]pyrimidine in step c. ¹HNMR (CD₃OD, 300 MHz, δ): 8.69 (s, 1H), 7.68 (d, J=3.6 Hz, 1H), 6.82 (d,J=3.6 Hz, 1H), 5.63-5.51 (m, 1H), 4.53-4.49 (m, 1H), 4.37 (dd, J=7.5,9.9 Hz, 1H), 4.20 (dd, J=7.5, 9.9 Hz, 1H), 2.90-2.80 (m, 1H), 2.77 (s,3H), 2.36-2.05 (m, 4H) ppm. LC/MS: R_(t)=0.50 min, ES⁺ 327 (FAstandard).

Example 32:{(1S,2S,4R)-2-Hydroxy-4-[4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}methylsulfamate (Compound I-28)

The title compound was prepared following the procedure described inExample 31a-b using chloro(2-phenylethyl)magnesium in step a. ¹H NMR(CD₃OD, 300 MHz, δ): 8.62 (s, 1H), 7.48 (d, J=3.9 Hz, 1H), 7.19-7.09 (m,5H), 6.57 (d, J=3.9 Hz, 1H), 5.55-5.46 (m, 1H), 4.49-4.46 (m, 1H), 4.35(dd, J=7.8, 9.6 Hz, 1H), 4.18 (dd, J=7.5, 9.6 Hz, 1H), 3.28-3.24 (m,2H), 3.10-3.04 (m, 2H), 2.88-2.80 (m, 1H), 2.31-2.01 (m, 4H) ppm. LC/MS:R_(t)=1.56 min, ES⁺417 (AA standard).

Example 33:{(1S,2S,4R)-2-Hydroxy-4-[4-(2-methyl-2-phenylpropyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentyl}methylsulfamate (Compound I-50)

The title compound was prepared following the procedure described inExample 31a-b using chloro(2-methyl-2-phenylpropyl)magnesium in step a.¹H NMR (400 MHz, CD₃OD, δ): 8.62 (s, 1H), 7.37-7.34 (m, 2H), 7.25-7.21(m, 2H), 7.16-7.12 (m, 1H), 6.15 (d, 1H), 5.56-5.47 (m, 1H), 4.49-4.48(br s, 1H), 4.37 (dd, J=7.6, 9.6 Hz, 1H), 4.22-4.17 (m, 1H), 2.93-2.87(m, 1H), 2.89-2.80 (m, 1H), 2.31-2.19 (m, 3H), 2.07-2.00 (m, 1H), 1.43(s, 6H) ppm. LC/MS: R_(t)=1.59 min, ES⁺ 445 (AA standard).

Example 34:{(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate and[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compounds I-9 and I-18) Step a:(1S,2S,4R)-4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

A solution ofN-(2,4-dimethoxybenzyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(123 mg, 0.238 mmol, prepared following the procedure described inExample 1a-f using 2,4-dimethoxybenzylamine in step c) and AcOH (1.00mL, 17.6 mmol) in water (0.500 mL) and THF (0.500 mL) were stirred at rtovernight. The reaction mixture was concentrated in vacuo andpurification by silica gel chromatography eluting with a gradient of 0to 10% MeOH in DCM afforded the title compound (43.0 mg, 73%). LC/MS:R_(t)=0.15 min, ES⁺ 249 (FA standard).

Step b:(1S,2S,4R)-4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol

To a solution of(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol(43.0 mg, 0.173 mmol) and imidazole (25.0 mg, 0.367 mmol) in dry DMF(2.00 mL) at 0° C. was added tert-butyldimethylsilyl chloride (29.0 mg,0.192 mmol). The solution was stirred at rt for 2 h and concentrated invacuo, the residue was dissolved in water and extracted with EtOAc. Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to afford the title compound (50.8 mg, 81%), whichwas taken on without further purification. LC/MS: R_(t)=1.38 min, ES⁺364 (FA standard).

Step c:(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentylacetate

To a solution of(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(125 mg, 0.345 mmol) in pyridine (2.00 mL) at 0° C. was added aceticanhydride (0.380 mL, 4.03 mmol). The solution was stirred at rtovernight. The reaction mixture was diluted with DCM and water. Thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography elutingwith a gradient of 0 to 50% EtOAc in hexanes to afford the titlecompound (47.8 mg, 31%). LC/MS: R_(t)=1.68 min, ES⁺ 447 (FA standard).

Step d:(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(hydroxymethyl)cyclopentylacetate

To a solution of(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl acetate (47.0 mg, 0.105 mmol) in a mixtureof THF (2.00 mL) and pyridine (2.00 mL) was added pyridine hydrofluoride(10 drops). After 2 h, additional pyridine hydrofluoride (15 drops) wasadded and the solution stirred for an additional 2 h. The reaction wasquenched via addition of saturated aqueous sodium bicarbonate solutionand extracted with EtOAc (2×50 mL). The combined organic extracts weredried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 0 to10% MeOH in DCM to afford the title compound (29.0 mg, 83%). LC/MS:R_(t)=0.76 min, ES⁺ 333 (FA standard).

Step e: (1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-{[(aminosulfonyl)oxy]methyl}cyclopentylacetate

A solution of(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(hydroxymethyl)cyclopentylacetate (63.0 mg, 0.190 mmol) and pyridine (0.0800 mL, 0.989 mmol) inAcCN (5.00 mL) at 0° C. was stirred for 15 min. A 0.641 M solutionchlorosulfonamide in AcCN (0.640 mL, 0.410 mmol, as prepared in 1j) wasthen added slowly. After 2 h another portion of the chlorosulfonamidesolution (0.72 mL, 0.462 mmol) was added and the reaction was stirredfor 1 hour. The reaction was then concentrated in vacuo and the residuewas purified by silica gel chromatography eluting with a gradient of 0to 10% MeOH in DCM to afford the title compound (78.0 mg, 100%). LC/MS:R_(t)=0.81 min, ES⁺ 412 (FA standard).

Step f:{(1S,2S,4R)-4-[4-(Acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate and[(1S,2S,4R)-4-(4-amino-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compounds I-9 and I-18)

To neat(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-{[(aminosulfonyl)oxy]methyl}cyclopentylacetate (78.0 mg, 0.190 mmol) was added a 7 M solution of ammonia inMeOH (5.00 mL) was stirred at rt overnight. LC/MS showed partialconversion to the intermediate mono-acetylated compound, the desiredproduct and some starting material remaining. The reaction mixture wasconcentrated in vacuo and the residue was purified by reverse phasechromatography to afford{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (0.900 mg, 1.3%) and[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (6.50 mg, 11%). Analytical data for{(1S,2S,4R)-4-[4-(acetylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (Compound I-9): ¹H NMR (400 MHz, CD₃OD, δ): 8.48 (s, 1H), 7.47(d, J=3.8 Hz, 1H), 6.82 (d, J=3.8, 1H), 5.65-5.48 (m, 1H), 4.60-4.45 (m,1H), 4.40-4.27 (m, 1H), 4.24-4.11 (m, 1H), 2.98-2.80 (m, 1H), 2.42-2.13(m, 6H), 2.18-1.93 (m, 1H) ppm. LC/MS: R_(t)=0.98 min, ES⁺ 370. (FAstandard). Analytical data for[(1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-18): ¹H NMR (400 MHz, CD₃OD, δ): 8.09 (s, 1H),7.30 (d, J=3.8 Hz, 1H), 6.66 (d, J=3.5 Hz, 1H), 5.51-5.41 (m, 1H),4.51-4.48 (m, 1H), 4.39-4.33 (m, 1H), 4.21-4.16 (m, 1H), 2.85-2.79 (m,1H), 2.33-2.18 (m, 3H), 2.09-2.00 (m, 1H) ppm. LC/MS: R_(t)=0.85 min,ES⁺ 328 (FA standard).

Example 35:((1S,2S,4R)-4-{4-[(1,3-Benzodioxol-5-ylmethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate Compound (I-26)

The title compound was prepared following the procedure described inExample 2a-j using 1-(1,3-benzodioxol-5-yl)methanamine in step f. ¹H-NMR(400 MHz, CD₃OD, δ): 8.09 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.81 (s, 1H),6.79 (d, J=9.9 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.56 (d, J=3.6 Hz, 1H),5.85 (s, 2H), 5.45-5.35 (m, 1H), 4.62 (s, 2H), 4.49-4.42 (m, 1H), 4.33(dd, J=7.6, 7.6 Hz, 1H), 4.16 (dd, J=7.3, 7.3 Hz, 1H), 2.86-2.70 (m,1H), 2.35-2.10 (m, 3H), 2.05-1.94 (m, 1H) ppm. LC/MS: R_(t)=1.07 min,ES⁺ 462 (FA standard).

Example 36:((1S,2S,4R)-2-Hydroxy-4-{4-[(1-naphthylmethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}cyclopentyl)methylsulfamate (Compound I-38)

The title compound was prepared following the procedure described inExample 2a-j using 1-(1-naphthyl)methanamine in step f. ¹H NMR (400 MHz,CD₃OD, δ): 8.13 (s, 1H), 8.11-8.05 (m, 1H), 7.89-7.84 (m, 1H), 7.77 (d,J=8.2 Hz, 1H), 7.52-7.43 (m, 3H), 7.42-7.35 (m, 1H), 7.15 (d, J=3.6 Hz,1H), 6.56 (d, J=3.3 Hz, 1H), 5.45-5.37 (m, 1H), 5.19 (s, 2H), 4.48-4.42(m, 1H), 4.34 (dd, J=7.6, 7.6 Hz, 1H), 4.17 (dd, J=7.3, 7.4 Hz, 1H),2.83-2.71 (m, 1H), 2.35-2.15 (m, 3H), 2.06-1.96 (m, 1H) ppm. LC/MS:R_(t)=1.24 min, 468 ES⁺ (FA standard).

Example 37:[(1S,2S,4R)-2-Hydroxy-4-(4-{[4-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-8)

The title compound was prepared following the procedure described inExample 2a-j using 1-[4-(trifluoromethyl)phenyl]methanamine in step f.¹H NMR (CD₃OD, 400 MHz, δ): 8.08 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.48(d, J=8.2 Hz, 2H), 7.18 (d, J=3.5 Hz, 1H), 6.58 (d, J=3.6 Hz, 1H),5.43-5.34 (m, 1H), 4.80 (s, 2H), 4.45 (br s, 1H), 4.33 (dd, J=2.1, 7.6Hz, 1H), 4.16 (dd, J=2.3, 7.4 Hz, 1H), 2.81-2.72 (m, 1H), 2.31-2.10 (m,3H), 2.05-1.97 (m, 1H) ppm. LC/MS: R_(t)=1.33 min, ES⁺ 486 (FAstandard).

Example 38:[(1S,2S,4R)-4-(4-{[4-Chloro-2-(trifluoromethyl)benzyl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-42)

The title compound was prepared following the procedure described inExample 2a-j using 1-[4-chloro-2-(trifluoromethyl)phenyl]methanamine instep f. ¹H NMR (CD₃OD, 400 MHz, δ): 8.11 (s, 1H), 7.70 (s, 1H),7.65-7.46 (m, 2H), 7.23 (d, J=3.6 Hz, 1H), 6.61 (d, J=3.4 Hz, 1H),5.48-5.39 (m, 1H), 4.93 (s, 2H), 4.49 (br s, 1H), 4.36 (dd, J=2.1, 7.6Hz, 1H), 4.20 (dd, J=2.3, 7.4 Hz, 1H), 2.87-2.74 (m, 1H), 2.38-2.12 (m,3H), 2.09-1.97 (m, 1H) ppm. LC/MS: R_(t)=1.29 min, ES⁺ 520 (FAstandard).

Example 39:((1S,2S,4R)-4-{4-[(2,4-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-19)

The title compound was prepared following the procedure described inExample 2a-j using 1-(2,4-dichlorophenyl)methanamine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.10 (s, 1H), 7.46 (s, 1H), 7.32 (d, J=8.3 Hz, 1H),7.29-7.20 (m, 2H), 6.61 (d, J=3.5 Hz, 1H), 5.54-5.37 (m, 1H), 4.92-4.74(s, 2H), 4.49 (br s, 1H), 4.37 (dd, J=2.1, 7.6 Hz, 1H), 4.19 (dd, J=2.4,7.3 Hz, 1H), 2.88-2.72 (m, 1H), 2.40-2.17 (m, 3H), 2.11-1.98 (m, 1H)ppm. LC/MS: R_(t)=1.37 min, ES⁺ 488 (FA standard).

Example 40:((1S,2S,4R)-4-{4-[(3,5-Dichlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-16)

The title compound was prepared following the procedure described inExample 2a-j using 1-(3,5-dichlorophenyl)methanamine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.10 (s, 1H), 7.35-7.23 (m, 3H), 7.19 (d, J=3.6 Hz,1H), 6.58 (d, J=3.6 Hz, 1H), 5.49-5.35 (m, 1H), 4.69 (s, 2H), 4.45 (brs, 1H), 4.33 (dd, J=2.1, 7.6 Hz, 1H), 4.16 (dd, J=2.4, 7.3 Hz, 1H),2.85-2.72 (m, 1H), 2.38-2.13 (m, 3H), 2.07-1.94 (m, 1H) ppm. LC/MS:R_(t)=1.38 min, ES⁺ 488 (FA standard).

Example 41:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-52) Step a: tert-Butyl[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate

(1R,2S)-1-Aminoindan-2-ol (1.83 g, 12.3 mmol) was dissolved in DCM (70.0mL) and TEA (3.42 mL, 24.5 mmol) was added. Di-tert-butyldicarbonate(2.81 g, 12.9 mmol) was added at rt and the reaction mixture was stirredfor 5 h. The solution was concentrated in vacuo and purified via silicagel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanesto afford the title compound (3.12 g, 100%). LC/MS: R_(t)=1.55 min, ES⁺250. (AA standard).

Step b: tert-Butyl[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate

A mixture of tert-butyl[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (680 mg, 2.73mmol), DMF (21.1 mL), barium monoxide (5.02 g, 32.7 mmol), bariumhydroxide (2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3 mmol) wasstirred overnight. LC/MS showed no starting material. The reaction wasquenched via addition of a saturated solution of sodium bicarbonate andwas extracted with DCM. The organic layer was washed with water (3×),dried over sodium sulfate and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 0 to50% EtOAc in hexanes to afford the title compound (178 mg, 25%). LC/MS:R_(t)=1.24 min, ES⁺ 264 (AA standard).

Step c: (1R,2S)-2-Methoxyindan-1-amine

To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate(253 mg, 0.961 mmol) was added a 4.00 M solution of hydrochloric acid in1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, afterwhich a white solid crashed out. The suspension was concentrated invacuo and co-evaporated with toluene to afford a white solid, which wasdissolved in water. The solution was adjusted to pH 10 via addition ofsodium carbonate. The mixture was then extracted with diethyl ether(3×30 mL) and the organic extracts were concentrated in vacuo to affordthe title compound (150 mg, 99%). LC/MS: R_(t)=0.85 min, ES⁺ 164 (AAstandard).

Step d:[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-52)

The title compound was prepared following the procedure described inExample 2a-j using (1R,2S)-2-methoxyindan-1-amine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.20 (s, 1H), 7.27-7.14 (m, 5H), 6.67 (d, J=3.6 Hz,1H), 5.90 (d, J=5.2 Hz, 1H), 4.49 (t, J=3.5 Hz, 1H), 4.37 (dd, J=7.6,9.7 Hz, 1H), 4.31-4.28 (m, 1H), 4.20 (dd, J=7.3, 9.7 Hz, 1H), 3.31-3.29(m, 4H) 3.19-3.05 (m, 2H), 2.85-2.77 (m, 1H), 2.37-2.20 (m, 3H),2.08-2.00 (m, 1H) ppm. LC/MS: R_(t)=1.46 min, ES⁺ 474 (AA standard).

Example 42:[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate and-[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compounds I-14 and I-21) Step a: 3,3-Dimethylindan-1-oneoxime

To a solution of 3,3-dimethylindan-1-one (1.16 g, 7.21 mmol) andhydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0 mL) wasadded a solution of sodium hydroxide (765 mg, 19.1 mmol) in water (10.0mL). The mixture was heated to 80° C. for 2 h. The cooled reaction wasconcentrated in vacuo and partitioned between DCM and water. The organiclayer was separated and concentrated in vacuo to afford the titlecompound as an oil (1.23 g, 97%). LC/MS: R_(t)=1.61 min, ES⁺ 176 (AAstandard).

Step b: 3,3-Dimethylindan-1-amine

3,3-Dimethylindan-1-one oxime (1.22 g, 6.96 mmol) was dissolved in MeOH(20.0 mL) and palladium (10 weight percent on carbon, 50% water wet, 148mg) was added. The reaction was placed under an atmosphere of hydrogenand was stirred overnight. The mixture was then filtered through Celite,washed through with MeOH and the filtrates concentrated in vacuo toafford the product as a grey oil (1.12 g, 100%). LC/MS: R_(t)=1.04 min,ES⁺ 162 (AA standard).

Step c:[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate and-[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compounds I-14 and I-21)

The title compounds were prepared following the procedure described inExample 1a-g and then Example 2i-j using 3,3-dimethylindan-1-amine instep 1c. The mixture was separated into its component diastereomers viachiral HPLC (Chiralpac-AS-RH, 20 mm ID×250 mm, 5 micron column elutingwith 55% water in AcCN with 0.1% AA at 6 mL/minute): Peak A—21.4 min,[(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate, R-enantiomer (Compound I-21). Peak B—22.6 min,[(1S,2S,4R)-4-(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]-methylsulfamate, S-enantiomer (Compound I-14). ¹H NMR (CD₃OD, 300 MHz, δ):8.16 (s, 1H), 7.28-7.10 (m, 5H), 6.63 (d, J=3.6 Hz, 1H), 5.93 (t, j=8.1Hz, 1H), 5.51-5.38 (m, 1H), 4.48 (br s, 1H), 4.37 (dd, J=7.6, 9.7 Hz,1H), 4.20 (dd, J=7.4, 9.6 Hz, 1H), 2.88-2.72 (m, 1H), 2.47 (dd, J=7.3,12.4 Hz, 1H), 2.37-2.19 (m, 3H), 2.03 (ddd, J=4.5, 9.2, 13.9 Hz, 1H),1.93 (dd, J=9.1, 12.3 Hz, 1H), 1.42 (s, 3H), 1.27 (s, 3H) ppm. LC/MS:R_(t)=1.66 min, ES⁺ 472 (AA standard).

Example 43:[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-14), Chiral synthesis Step a:(2R)-2-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol

To a solution of 3,3-dimethylindan-1-one (925 mg, 5.77 mmol) and(R)-(−)-2-phenylglycinol (893 mg, 6.51 mmol) in toluene (10.0 mL) wasadded p-toluenesulfonic acid monohydrate (62.5 mg, 0.328 mmol). Thereaction was heated to reflux under an atmosphere of nitrogen for 90min. At this point, the mixture was cooled and diluted with toluene(10.0 mL). The mixture was washed with saturated aqueous sodiumbicarbonate solution and water. The organic layer was concentrated invacuo and the residue was dissolved in THF (10.0 mL) and cooled to 0° C.Acetic acid (1.13 mL, 19.9 mmol) was added, followed by sodiumborohydride (251 mg, 6.64 mmol) and the reaction was allowed to warm tort overnight. The mixture was partitioned between DCM and saturatedaqueous sodium bicarbonate solution. The organic layer was concentratedand silica gel chromatography eluting with a gradient of 5 to 35% EtOAcin DCM afforded the title compound (1.49 g, 74%). LC/MS: R_(t)=1.92 min,ES⁺ 282 (AA standard).

Step b: (1S)-3,3-Dimethylindan-1-amine

A solution of(2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol(1.44 g, 5.13 mmol) in MeOH (40.0 mL) was added to a stirred solution oflead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL) at 0° C.dropwise over 20 min. After stirring for 45 min, the reaction wasquenched via addition of a 10% solution of sodium carbonate in water(76.0 mL) and the mixture was stirred for 10 min. DCM (200 mL) was thenadded and the layers were separated. The aqueous layer was extractedwith DCM (50.0 mL). The combined organic layers were concentrated invacuo and the residue was dissolved in ethanol (190 mL) and treated witha 10.4 M aqueous solution of hydrochloric acid (5.70 mL, 59.3 mmol). Theresulting mixture was then heated to reflux for 16 h. The cooledreaction was concentrated in vacuo and partitioned between water (150mL) and diethyl ether (50.0 mL). The aqueous layer was adjusted to pH 10via addition of sodium carbonate and extracted with diethyl ether(3×50.0 mL). The combined organic layers were concentrated in vacuo andsilica gel chromatography eluting with a gradient of 0 to 10% MeOH inDCM to afford the title compound as a pale yellow oil (420 mg, 51%). ¹HNMR (CD₃OD, 300 MHz, δ): 7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H), 2.38 (dd,J=7.1, 12.4 Hz, 1H), 1.73 (br s, 2H), 1.60 (dd, J=8.7, 12.4 Hz, 1H),1.39 (s, 3H), 1.19 (s, 3H) ppm.

Step c:[(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-14)

The title compound was prepared following the procedure described inExample 1a-g and then Example 2i-j using (1S)-3,3-dimethylindan-1-aminein step 1c. Chiral HPLC showed co-elution with the compound synthesizedin Example 42c, Peak B. Analytical data identical to Example 42c.

Example 44:[(1S,2S,4R)-4-(4-{[(1S)-5-Chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate, Potassium Salt (Compound I-27)

The title compound was prepared following the procedure described inExample 43a-b and then Example 2f-j using 5-chloroindan-1-one in step43a and (1S)-5-chloroindan-1-amine in step 2f. The potassium salt wasformed following the procedure described in Example 11. ¹H NMR (CD₃OD,300 MHz, δ): 8.17 (s, 1H), 7.28-7.10 (m, 4H), 6.62 (d, J=3.6 Hz, 1H),5.82 (t, J=7.7 Hz, 1H), 5.44 (qd, J=4.6, 8.3 Hz, 1H), 4.48 (br s, 1H),4.37 (dd, J=7.6, 9.7 Hz, 1H), 4.19 (dd, J=7.4, 9.7 Hz, 1H), 4.09 (q,J=7.1 Hz, 1H), 3.05 (ddd, J=3.3, 8.6, 15.9 Hz, 1H), 2.98-2.71 (m, 2H),2.64 (dtd, J=3.5, 7.7, 11.2 Hz, 1H), 2.38-2.14 (m, 3H), 2.05 (dd, J=4.4,8.6 Hz, 1H) ppm. LC/MS: R_(t)=1.58 min, ES⁺ 478 (AA standard).

Example 45:[(1S,2S,4R)-4-(4-{[(1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-36)

The title compound was prepared following the procedure described inExample 44 using 5-fluoroindan-1-one. ¹H NMR (CD₃OD, 400 MHz, δ): 8.17(s, 1H), 7.25-7.19 (m, 2H), 6.99-6.85 (m, 2H), 6.63 (d, J=3.6 Hz, 1H),5.81 (t, J=7.5 Hz, 1H), 5.49-5.41 (m, 1H), 4.49 (t, J=3.6 Hz 1H), 4.37(dd, J=7.6, 9.7 Hz, 1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H), 3.12-3.02 (m,1H), 2.95-2.87 (m, 1H), 2.84-2.75 (m, 1H), 2.69-2.61 (m, 1H), 2.36-2.19(m, 3H), 2.10-1.97 (m, 2H) ppm. LC/MS: R_(t)=1.56 min, ES⁺ 462 (AAstandard).

Example 46:[(1S,2S,4R)-4-(4-{[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-33)

The title compound was prepared following the procedure described inExample 44 using 5-bromoindan-1-one. ¹H NMR (CD₃OD, 400 MHz, δ): 8.17(s, 1H), 7.42 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.19-7.14 (m, 2H), 6.63(d, J=3.6 Hz, 1H), 5.82 (t, J=7.8 Hz, 1H), 5.49-5.41 (m, 1H), 4.49 (brs, 1H), 4.38 (dd, J=7.6, 9.7 Hz, 1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H),3.08-3.01 (m, 1H), 2.96-2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59 (m,1H), 2.36-2.20 (m, 3H), 2.08-1.99 (m, 2H) ppm. LC/MS: R_(t)=1.64 min,ES⁺ 524 (AA standard).

Example 47:((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methylsulfamate (Compound I-5) Step a:(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-ol

To a solution of (1S,5S)-5-(hydroxymethyl)cyclopent-2-en-1-ol (1.14 g,9.99 mmol) in DCM (50.0 mL) was added TEA (4.18 mL, 30.0 mmol) and DMAP(60.0 mg, 0.491 mmol). The solution was cooled to 0° C.,tert-butylchlorodiphenylsilane (3.90 mL, 15.0 mol) was added and themixture was stirred at rt for 2 h. TLC indicated complete conversion,and the reaction was quenched by addition of MeOH (1.00 mL).Concentration in vacuo and silica gel chromatography eluting with agradient of 0 to 100% EtOAc in hexanes afforded the title compound (2.88g, 86%). LC/MS: R_(t)=2.51 min, ES⁺ 353 (AA standard).

Step b:(5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-one

(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-ol(460 mg, 1.30 mmol) was dissolved in DCM (15.0 mL) and pyridiniumdichromate (1.47 g, 3.91 mmol) was added. The mixture was stirred at rtovernight, at which point LC/MS indicated complete conversion. Themixture was diluted with DCM (15.0 mL), filtered and concentrated invacuo. Silica gel chromatography eluting with 0 to 50% EtOAc in hexanesafforded the title compound (400 mg, 79%). LC/MS: R_(t)=2.42 min, ES⁺351 (AA standard).

Step c:(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-1-methlcyclopent-2-en-1-ol

A solution of (5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-one (250 mg, 0.713 mmol) in diethylether (10.0 mL) under an atmosphere of nitrogen was cooled to −40° C.and a 1.60 M solution of methyllithium in diethyl ether (0.579 mL, 0.926mmol) was added slowly and the mixture was stirred at −40° C. for 3 h.TLC indicated complete conversion, and the reaction was quenched viaaddition of saturated aqueous ammonium chloride (5.00 mL), extractedwith EtOAc (3×10.0 mL), dried over MgSO₄, filtered, and concentrated invacuo. Silica gel chromatography eluting with a gradient of 0 to 50%EtOAc in hexanes afforded the title compound (190 mg, 73%).Stereochemistry of the product was confirmed using ROESY analysis.LC/MS: R_(t)=2.55 min, ES⁺ 367 (AA standard).

Step d: (1S,5S)-5-(Hydroxymethyl)-1-methylcyclopent-2-en-1-ol

To a solution of(1S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-methylcyclopent-2-en-1-ol(560 mg, 1.53 mmol) in THF (29.5 mL) at 0° C. was added 1.00 M oftetra-n-butylammonium fluoride in THF (3.06 mL, 3.06 mmol). The mixturewas stirred at rt for 2 h, at which point the solvent was concentratedin vacuo and the residue was purified by silica gel chromatographyeluting with a gradient of 50 to 100% EtOAc in hexanes to afford thetitle compound (181 mg, 92%). LC/MS: R_(t)=0.76 min, ES⁺ 129 (AAstandard).

Step e:(1S,2R,3S,5S)-3-(Hydroxymethyl)-2-methyl-6-oxabicyclo[3.1.0]hexan-2-ol

To a solution of (1S,5S)-5-(hydroxymethyl)-1-methylcyclopent-2-en-1-ol(0.181 g, 0.00141 mol) in DCM (18.0 mL) was added sodium bicarbonate(237 mg, 2.82 mmol) and the mixture was cooled to 0° C. To this mixturewas added 3-chloroperbenzoic acid (380 mg, 1.69 mmol) and the reactionwas stirred at rt for 4 h. The solvent was removed in vacuo and silicagel chromatography eluting with a gradient of 0 to 100% EtOAc in DCMafforded the title compound (200 mg, 98%). LC/MS: R_(t)=0.52 min, ES⁺145 (AA standard).

Step f:(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)-1b-methylhexahydrooxireno[4,5]-cyclopenta[1,2-d][1,3]dioxine

To a solution of(1S,2R,3S,5S)-3-(hydroxymethyl)-2-methyl-6-oxabicyclo[3.1.0]hexan-2-ol(200 mg, 1.39 mmol) in DCM (13.0 mL) at 0° C. was addeddimethoxy(4-methoxyphenyl)methane (0.709 mL, 4.16 mmol) followed bypyridinium p-toluenesulfonate (35.0 mg, 0.139 mmol) and the mixture wasstirred at rt overnight. TLC showed complete conversion. Silica gelchromatography eluting with a gradient of 0 to 50% EtOAc in hexanesafforded the title compound (215 mg, 59%). LC/MS: R_(t)=1.72 min, ES⁺263 (AA standard).

Step g:((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methylsulfamate (Compound I-5)

The title compound was prepared following the procedure described inExample 1d-i using(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)-1b-methylhexahydrooxireno[4,5]cyclopenta-[1,2-d][1,3]dioxineand 4-chlorobenzylamine in step d. ¹H NMR (CD₃OD, 400 MHz, δ): 8.20 (s,1H), 7.46 (d, J=3.6 Hz, 1H), 7.37 (s, 4H), 6.82 (d, J=3.6 Hz, 1H),5.48-5.40 (m, 1H), 4.78 (s, 2H), 4.41 (dd, J=6.0, 10.0 Hz, 1H), 4.14(dd, J=8.2, 10.0 Hz, 1H), 2.69-2.64 (m, 1H), 2.39-2.16 (m, 4H), 1.47 (s,3H) ppm. LC/MS: R_(t)=1.55 min, ES⁺ 466 (AA standard).

Example 48:(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxy-2-methylcyclopentyl)methylsulfamate (Compound I-30)

The title compound was prepared following the procedure described inExample 47 using (S)-(+)-1-aminoindan in step g. ¹H NMR (CD₃OD, 400 MHz,δ): 8.25 (s, 1H), 7.48 (d, J=3.6 Hz, 1H), 7.34-7.23 (m, 4H), 6.89 (d,J=3.6 Hz, 1H), 5.61-5.56 (m, 1H), 5.50-5.43 (m, 1H), 4.42 (dd, J=6.0,10.0 Hz, 1H), 4.15 (dd, J=8.0, 10.0 Hz, 1H), 3.18-3.10 (m, 1H),3.03-2.97 (m, 1H), 2.75-2.64 (m, 1H), 2.39-2.07 (m, 5H), 1.48 (s, 3H)ppm. LC/MS: R_(t)=1.57 min, ES⁺ 458 (AA standard).

Example 49:[(1S,2S,4R)-4-(4-{[2-(difluoromethoxy)benzyl]amino}-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-2)

The title compound was prepared following the procedure described inExample 2a-j, using 2-difluoromethoxybenzylamine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.10 (s, 1H), 7.35-7.26 (m, 2H), 7.22 (d, J=3.7 Hz,1H), 7.17-7.13 (m, 2H), 6.87 (t, J=74.2 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H),5.45-5.20 (m, 1H), 4.80 (s, 2H), 4.49-4.47 (m, 1H), 4.36 (dd, J=7.6, 9.7Hz, 1H), 4.19 (dd, J=7.3, 9.7 Hz, 1H), 2.86-2.75 (m, 1H), 2.35-2.19 (m,3H), 2.07-2.00 (m, 1H) ppm. LC/MS: R_(t)=1.03 min, ES⁺ 484 (FAstandard).

Example 50:[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-44) Step a:5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]-dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(363 mg, 0.995 mmol, as prepared in Example 1a-f) in DCM (15.0 mL) wasadded N-iodosuccinimide (256 mg, 1.14 mmol), and the mixture was stirredat rt overnight. Silica gel chromatography eluting with a gradient of 25to 100% EtOAc in hexanes afforded the title compound (253 mg, 52%).LC/MS: R_(t)=2.03 min, ES⁺ 492 (AA standard).

Step b:7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine

To a suspension of5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(337 mg, 0.685 mmol), copper(I) iodide (26.0 mg, 0.137 mmol),dichlorobis(triphenylphosphine)-palladium(II) (48.0 mg, 0.0684 mmol) andDIPEA (0.240 mL, 1.38 mmol) in DMF (20.0 mL) was addedethynyltrimethylsilane (188 mg, 1.91 mmol) and the mixture was stirredat rt overnight. The reaction mixture was quenched via addition ofsaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. Silica gel chromatography eluting with a gradientof 0 to 75% EtOAc in hexanes afforded the title compound (314 mg, 99%).LC/MS: R_(t)=2.38 min, ES⁺ 462 (AA standard).

Step c:5-ethynyl-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]-dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine

Potassium carbonate (191 mg, 1.38 mmol) was added to a solution of7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine(314 mg, 0.680 mmol) in MeOH (10.0 mL), and the mixture was stirred atrt overnight. The reaction mixture was diluted with EtOAc, washed withsaturated aqueous sodium bicarbonate solution, dried over MgSO₄,filtered, and concentrated in vacuo to afford the title compound as anoil (215 mg, 81%). LC/MS: R_(t)=1.94 min, ES⁺ 390 (AA standard).

Step d:[(1S,2S,4R)-4-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-44)

The title compound was prepared following the procedure described inExample 1g-j, using5-ethynyl-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidinein step g. ¹H NMR (CD₃OD, 400 MHz, δ): 8.63 (s, 1H), 7.87 (s, 1H),5.47-5.58 (m, 1H), 4.51-4.47 (m, 1H), 4.36 (dd, J=7.5, 9.5 Hz, 1H), 4.19(dd, J=7.5, 10.0 Hz, 1H), 3.65 (s, 1H), 3.48-3.46 (m, 1H), 3.13-3.11 (m,1H), 2.90 (s, 3H), 2.33-2.20 (m, 2H), 2.00-2.12 (m, 1H) ppm. LC/MS:R_(t)=1.16 min, ES⁺ 351 (AA standard).

Example 51:[(1S,2S,4R)-4-(4-{[(1S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-61)

The title compound was prepared following the procedure described inExample 2a-j using (R)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in stepf. 1H NMR (CD₃OD, 400 MHz, δ): 8.27 (s, 1H), 7.44 (d, J=3.21 Hz, 1H)7.30-7.24 (m, 1H), 7.15 (d, J=7.5, 1H), 7.02 (t, J=8.64, 8.64 Hz, 1H),6.86 (d, J=2.93 Hz, 1H), 5.67 (t, J=6.99, 6.99 Hz, 1H), 5.56-5.48 (m,1H), 4.52-4.48 (m, 1H), 4.37 (dd, J=9.76, 7.49 Hz, 1H), 4.19 (dd,J=9.75, 7.44 Hz, 1H), 3.22-3.14 (m, 1H), 3.02-2.93 (m, 1H), 2.90-2.70(m, 2H), 2.38-2.04 (m, 5H), ppm. LC/MS: R_(t)=1.10 min, ES⁺ 462 (FAstandard).

Example 52:[(1R,2R,4S)-4-(4-{[(1S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-62)

The title compound was prepared following the procedure described inExample 2a-j using (S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl amine instep f. 1H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.17 (d, J=3.8 Hz,1H), 6.99 (m, 1H), 6.89 (m, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.05 (t, J=5.5Hz, 1H), 5.48-5.41 (m, 1H), 4.48 (t, J=6.8 Hz, 1H), 4.36 (dd, J=7.5, 9.8Hz, 1H), 4.19 (dd, j=7.3, 9.8 Hz, 1H), 3.20-3.11 (m, 1H), 2.98-2.89 (m,1H), 2.84-2.75 (m, 1H), 2.70-2.60 (m, 1H), 2.35-2.20 (m, 3H), 2.19-2.09(m, 1H), 2.07-1.99 (m, 1H). LC/MS: R_(t)=1.07 min, ES⁺ 480 (FAstandard).

Example 53:[(1S,2S,4R)-4-(4-{[(1R)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-63)

The title compound was prepared following the procedure described inExample 2a-j using (R)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in stepf. ¹H NMR (CD₃OD, 400 MHz, δ): 8.18 (s, 1H), 7.24-7.12 (m, 4H), 6.64 (d,J=3.6 Hz, 1H), 5.91 (t, J=8.1 Hz, 1H), 5.51-5.39 (m, 1H), 4.49 (t, J=7.2Hz, 1H), 4.37 (dd, J=7.7, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H),3.18-3.07 (m, 1H), 2.98-2.85 (m, 1H), 2.84-2.74 (m, 1H), 2.72-2.60 (m,1H), 2.38-2.17 (m, 3H), 2.11-1.98 (m, 2H). LC/MS: R_(t)=1.16 min, ES⁺478 (FA standard).

Example 54:((1S,2S,4R)-4-(4-((S)-4-chloro-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methylsulfamate (Compound I-64)

The title compound was prepared following the procedure described inExample 2a-j using (S)-4-chloro-2,3-dihydro-1H-inden-1-yl amine in stepf. ¹H NMR (CD₃OD, 400 MHz, δ): 8.30 (s, 1H), 7.52 (br s, 1H), 7.38-7.23(m, 3H), 6.93 (br s, 1H), 5.69-5.50 (m, 2H), 4.54-4.47 (m, 1H), 4.37(dd, J=7.3, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.5 Hz, 1H), 3.25-3.15 (m,1H), 3.07-2.96 (m, 1H), 2.92-2.82 (m, 1H), 2.82-2.71 (m, 1H), 2.40-2.06(m, 5H). LC/MS: R_(t)=1.64 min, ES⁺ 478 (AA standard).

Example 55:[(1S,2S,4R)-4-(4-{[(1R)-4-bromo-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-65)

The title compound was prepared following the procedure described inExample 44 using 4-bromoindan-1-one. ¹H-NMR (400 MHz, MeOD, δ): 8.17 (s,1H), 7.39 (d, J=7.9 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.19 (d, J=3.7 Hz,1H), 7.08 (t, J=7.7 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H), 5.96 (t, J=7.8 Hz,1H), 5.44 (m, 1H), 4.48 (t, J=3.5 Hz, 1H), 4.37 (dd, J=7.6 Hz, 9.7 Hz,1H), 4.19 (dd, J=7.3 Hz, 9.7 Hz, 1H), 3.09 (ddd, J=3.2 Hz, 9.1 Hz, 16.3Hz, 1H), 2.89 (td, J=8.4 Hz, 16.6 Hz, 1H), 2.79 (m, 1H), 2.65 (dtd,J=3.3 Hz, 8.0 Hz, 12.7 Hz, 1H), 2.27 (m, 3H), 2.05 (m, 2H). LC/MS:R_(t)=1.66 min, ES⁺ 524 (AA standard).

Example 56:[(1R,2R,4S)-4-(4-{[(1S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-66)

The title compound was prepared following the procedure described inExample 44 using 7-fluoroindan-1-one. ¹H NMR (CD₃OD, 400 MHz, δ): 8.17(s, 1H), 7.29-7.22 (m, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.09 (d, J=7.5 Hz,1H), 6.86 (t, J=9.0 Hz, 1H), 6.61 (d, J=3.8 Hz, 1H), 6.00 (t, J=7.5 Hz,1H), 5.48-5.39 (m, 1H), 4.48 (t, J=6.8 Hz, 1H), 4.36 (dd, J=7.5, 9.8 Hz,1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H), 3.20-3.11 (m, 1H), 2.97-2.88 (m, 1H),2.85-2.74 (m, 1H), 2.65-2.55 (m, 1H), 2.36-2.18 (m, 3H), 2.14-1.98 (m,1H). LC/MS: R_(t)=1.16 min, ES⁺ 462 (formic acid standard).

Step a: 1-(4-chlorophenyl)-3-methylbutan-2-ol

Magnesium (5.02 g, 0.206 mol) was covered in dry ether (50 mL, 0.5 mol)under an atmosphere of nitrogen. Iodine (0.254 g, 0.001 mol) was addedto the reaction, followed by approximately 1 mL of a solution of1-chloro-4-(chloromethyl)-benzene (32.20 g, 0.200 mol) in ether (25.0mL, 0.238 mol). An exotherm was noted and the mixture reached reflux.The slow addition of solution was continued over 90 minutes to maintaina gentle reflux. On completion of the addition, the reaction was heatedfor 30 minutes at 45° C. The reaction was then cooled to 0° C.Isobutyraldehyde (25.19 mL, 0.2774 mol) in Ether (20 mL, 0.2 mol) wasthen added slowly over 2 hours at 0° C. On completion of the additionthe reaction was allowed to warm to room temperature and stir overnight.The reaction was then quenched with ice (200 g) and acidified with 2MHCl (100 mL). The organic phase was separated and the aqueous wasextracted twice with more ether. The combined organic phase wasevaporated and the residue was purified by silica gel chromatography,eluting with 0 to 10% methanol in dichloromethane to yield the product,17.8 g (45%). ¹H NMR (300 MHz, CDCl₃, δ): 7.22 (m, 4H), 3.56 (m, 1H),2.81 (dd, J=3.3 Hz, 13.7 Hz, 1H), 2.58 (dd, J=9.4 Hz, 13.7 Hz, 1H), 1.74(dt, J=6.5 Hz, 12.9 Hz, 1H), 1.45 (s, 1H), 1.00 (s, 3H), 0.98 (s, 3H).

Step b: 6-chloro-1,1-dimethylindane

Concentrated sulfuric acid (45.0 mL) was added to water (5.00 mL)carefully and allowed to cool down to room temperature.1-(4-chlorophenyl)-3-methylbutan-2-ol (17.8 g, 0.0896 mol) was addedportionwise over 30 minutes. After the addition, the mixture was left tostir at room temperature for 2 hours. The mixture was then poured ontoice and the aqueous layer was extracted with ether. The organic phasewas washed water and then dried over magnesium sulphate and concentratedto yield crude product. The residue was purified by filtration through aplug of silica, eluting with dichloromethane, to yield the product, 12.6g (78%). ¹H-NMR (400 MHz, CDCl₃, δ): 7.10 (m, 3H), 2.85 (t, J=7.2 Hz,1H), 1.94 (t, J=7.2 Hz, 1H), 1.25 (s, 6H).

Step c: 5-chloro-3,3-dimethylindan-1-one

6-chloro-1,1-dimethylindane (2.19 g, 0.0121 mol) was dissolved inacetone (50 mL), and 1.41 M solution of magnesium sulfate in water (9.02mL) was added, followed by potassium permanganate (3.83 g, 0.0242 mol).The mixture was stirred at room temperature overnight. 1:1water:isopropanol was then added to the mixture and this was stirred for1 hour. The mixture was then evaporated to an aqueous residue and ethylacetate was added. The mixture was filtered, washing the collectedsolids with EtOAc, and the filtrates were separated. The organic phasewas concentrated, and the residue was purified by silica gelchromatography, eluting with 20 to 100% dichloromethane in hexanes toyield the product, 1.25 g (46%). ¹H-NMR (400 MHz, CDCl₃, δ) 7.62 (d,J=8.3 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.34 (dd, J=1.8 Hz, 8.1 Hz, 1H),2.60 (s, 2H), 1.42 (s, 6H).

Step d:((1S,2S,4R)-4-(4-((S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methylsulfamate (Compound I-67)

The title compound was prepared following the procedure described inExample 44 using 5-chloro-3,3-dimethylindan-1-one. ¹H NMR (CD₃OD, 400MHz, δ): 8.16 (bs, 1H); 7.22 (bs, 1H); 7.20 (d, J=3.77 Hz, 1H);7.16-7.14 (m, 2H); 6.62 (d, J=3.51 Hz, 1H); 5.91 (t, J=7.28 Hz, 1H);5.50-5.40 (m, 1H); 4.49 (t, J=3.01 Hz, 1H); 4.33 (dd, J=7.78, 2.00 Hz);4.16 (dd, J=7.28 Hz, 2.51 Hz); 2.85-2.74 (m, 1H); 2.53-2.45 (m, 1H);2.37-2.18 (m, 3H); 2.08-1.94 (m, 2H); 1.43 (s, 3H); 1.28 (s, 3H). LC/MS:R_(t)=1.42 min, ES⁺ 506 (FA standard).

Example 57:((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-68)

The title compound was prepared following the procedure described inExample 1a-g and then Example 2i-j using (S)-1-aminoindane and4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine in step 1c. ¹H NMR (CD₃OD,400 MHz, δ): 8.18 (s, 1H), 7.30-7.14 (m, 5H), 5.82 (t, J=7.8, 7.8 Hz,1H), 5.55-5.45 (m, 1H), 4.48-4.44 (m, 1H), 4.35 (dd, J=9.72, 7.37 Hz,1H), 4.18 (dd, J=9.72, 7.37 Hz, 1H), 3.11-3.02 (m, 1H), 2.98-2.88 (m,1H), 2.88-2.73 (m, 1H), 2.71-2.63 (m, 1H), 2.34-2.16 (m, 3H), 2.10-1.96(m, 2H) ppm. LC/MS: R_(t)=1.50 min, ES⁺ 462 (FA standard).

Example 58:[(1S,2S,4R)-4-(5-fluoro-4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-69)

The title compound was prepared following the procedure described inExample 1a-g and then Example 2i-j using (1R,2S)-2-methoxyindan-1-amineand 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine in step 1c. ¹H NMR(CD₃OD, 400 MHz, δ): 8.20 (s, 1H), 7.27-7.13 (m, 4H), 7.10 (d, J=2.3 Hz,1H), 5.88 (d, J=5.3 Hz, 1H), 5.49 (br s, 1H), 4.47 (t, J=7.3 Hz, 1H),4.35 (dd, J=7.5, 9.8 Hz, 1H), 4.31-4.28 (m, 1H), 4.18 (dd, J=7.5, 9.8Hz, 1H), 3.39 (s, 3H), 3.19-3.03 (m, 2H), 2.83-2.75 (m, 1H), 2.34-2.16(m, 3H), 2.03-1.97 (m, 1H). LC/MS: R_(t)=1.55 min, ES' 492 (formic acidstandard).

Example 59:(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-70)

The title compound was prepared following the procedure described inExample 41a-d, using ethyl iodide in step b. ¹H NMR (CD₃OD, 400 MHz, δ):8.19 (s, 1H), 7.29-7.17 (m, 5H), 6.65 (d, J=3.6 Hz, 1H), 5.73 (d, J=5.1Hz, 1H), 5.50-5.44 (m, 1H), 4.49-4.48 (m, 1H), 4.42-4.35 (m, 2H), 4.20(dd, J=7.3, 9.8 Hz, 1H), 3.66-3.56 (m, 2H), 3.51-3.43 (m, 1H), 3.12 (d,J=3.8 Hz, 2H), 2.81 (m, 1H), 2.37-2.20 (m, 3H), 2.08-2.03 (m, 1H),1.70-1.56 (m, 1H), 1.53-1.36 (m, 1H), 1.05 (t, J=7.0 Hz), 0.97-0.90 (m,2H) ppm. LC/MS: R_(t)=1.59 min, ES⁺ 488 (AA standard).

Example 60:(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-54)

The title compound was prepared following the procedure described inExample 41a-d, using isopropyl iodide in step b. ¹H NMR (CD₃OD, 400 MHz,δ): 8.20 (s, 1H), 7.31-7.18 (m, 5H), 6.67 (d, J=3.6 Hz, 1H), 5.82 (d,J=5.4 Hz, 1H), 5.51-5.44 (m, 1H), 4.53-4.48 (m, 2H), 4.37 (dd, J=7.6,9.7 Hz, 1H), 4.20 (dd, J=7.3, 9.7 Hz, 1H), 3.67-3.61 (m, 1H), 3.18-3.02(m, 2H), 2.84-2.78 (m, 1H), 2.37-2.00 (m, 4H), 1.09 (d, J=6.1 Hz, 3H),0.93 (d, J=6.1 Hz, 3H). LC/MS: R_(t)=1.68 min, ES⁺ 502 (AA standard).

Example 61:[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-71)

The title compound was prepared following the procedure described inExample 2a-j using (1R,2S)-2-hydroxyindan-1-amine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.18 (s, 1H), 7.29-7.16 (m, 5H), 6.68 (d, J=3.8 Hz,1H), 5.77 (d, J=4.5 Hz, 1H), 5.53-5.40 (m, 1H), 4.72-4.68 (m, 1H),4.51-4.47 (m, 1H), 4.37 (dd, J=7.5, 9.5 Hz, 1H), 4.21 (dd, J=7.5, 9.8Hz, 1H), 3.24-3.18 (m, 1H), 3.02-2.95 (m, 1H), 2.87-2.78 (m, 1H),2.39-2.19 (m, 3H), 2.09-2.00 (m, 1H). LC/MS: R_(t)=0.90 min, ES⁺ 460(formic acid standard).

Example 62:[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-72)

Step a:2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione

A suspension of (1R,2R)-1-aminoindan-2-ol (1.40 g, 0.00938 mol),phthalic anhydride (1.39 g, 0.00938 mol), and N,N-diisopropylethylamine(1.63 mL, 0.00935 mol) in toluene (141 mL) in a 250 mL round bottomflask equipped with a Dean-Stark trap and condenser was stirred atreflux under an atmosphere of nitrogen 18 h. The reaction mixture wascooled to rt. TLC showed complete conversion of starting material to ahigher R_(f) spot. ¹H NMR of an aliquot sample partitioned between EtOAcand water confirmed that reaction was complete. The reaction mixture wasconcentrated to a pale white and pale brown solid, redissolved in EtOAc(25 mL), washed with 1N HCl (2×10 mL), aqueous saturated NaHCO₃ (1×10mL), and brine (1×10 mL), dried over Na₂SO₄, filtered, concentrated, anddried on high vacuum to give the product as an off-white solid (2.53 g,97%). ¹H NMR (CDCl₃ 400 MHz, δ): 7.86-7.84 (m, 2H), 7.74-7.72 (m, 2H),7.26-7.25 (m, 2H), 7.20-7.14 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 5.67 (d,J=6.3 Hz, 1H), 5.14 (m, 1H), 3.58 (dd, J=7.5, 16.1 Hz, 1H), 2.97 (dd,J=6.8, 15.8 Hz, 1H), 2.12 (s, 1H) ppm.

Step b:2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione

To a solution of2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione(0.860 g, 0.00308 mol) in THF (30 mL) at 0° C. under an atmosphere ofnitrogen was added a 1.0 M solution of lithium hexamethyldisilazide inTHF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 20minutes, followed by the addition of methyl iodide (0.575 mL, 0.00924mol). The cold bath was removed, and the reaction mixture was allowed tostir and warm to rt over 18 h. The reaction was monitored by ¹H NMR. Thereaction mixture was then re-cooled to 0° C. To the reaction mixture wasadded 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL,0.00339 mol). The reaction mixture was stirred for 15 minutes, followedby addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath wasremoved, and the reaction mixture was allowed to stir at rt for 22 h. ¹HNMR indicated 80:20 product/starting material. The reaction was quenchedwith aqueous 1N HCl solution and then concentrated in vacuo. The residuewas partitioned between EtOAc and water. The organic phase was washedwith saturated NaHCO₃ and brine, dried over Na₂SO₄, filtered, andconcentrated. The oil was purified by silica gel chromatography, elutingwith a gradient of hexanes to 10% EtOAc in hexanes) to obtain product(4.18 g, 46%). LC/MS: R_(t)=1.90 min, ES⁺ 294 (AA standard).

Step c: (1R,2R)-2-methoxyindan-1-amine

To a mixture of2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione(4.13 g, 0.00141 mol) in ethanol (3.38 mL) under an atmosphere of argonwas added hydrazine (0.0442 mL, 0.0580 mol). The reaction mixture wasallowed to stir at rt overnight. White solid byproduct crashed out ofsolution. TLC showed no starting material. The reaction mixture wasconcentrated, and the residue was suspended in DCM and filtered. Thefiltrate was concentrated in vacuo. ¹H NMR showed that the reaction hadnot gone to completion. The yellow oil was therefore stirred at refluxfor 3 h. LCMS confirmed reaction was complete. The reaction mixture wascooled to rt, concentrated in vacuo, triturated with DCM, filtered, andthe filtrate was concentrated in vacuo to give product as a yellow oil(0.154 g, 64%). LC/MS: R_(t)=0.68 min, ES⁺ 164 (AA standard).

Step d:[(1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2R-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (Compound I-70)

The title compound was prepared following the procedure described inExample 2a-j using (1R,2R)-2-methoxyindan-1-amine in step f. ¹H NMR(CD₃OD, 400 MHz, δ): 8.18 (s, 1H), 7.22-7.19 (m, 3H), 7.15-7.14 (m, 2H),6.63 (d, J=3.4 Hz, 1H), 5.84 (d, J=5.9 Hz, 1H), 5.49-5.51 (m, 1H),4.50-4.48 (m, 1H), 4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.25-4.18 (m, 2H), 3.47(s, 3H), 3.37 (dd, J=7.3, 15.8 Hz, 1H), 2.87 (dd, J=6.8, 15.7 Hz, 1H),2.83-2.77 (m, 1H), 2.33-2.20 (m, 3H), 2.07-2.00 (m, 1H), 1.94 (s, 1H)ppm. LC/MS: R_(t)=1.51 min, ES⁺ 474 (AA standard).

Example 63:2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide(Compound I-59) Step a:7-[(1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy-4-([tert-butyl(dimethyl)silyl]oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol(0.787 g, 0.00216 mol), 1H-imidazole (0.588 g, 0.00864 mol) andN,N-dimethylaminopyridine (0.022 g, 0.00018 mol) were dissolved inN,N-dimethylformamide (24 mL) under an atmosphere of nitrogen. After 2hours, additional tert-butyldimethylsilyl chloride (0.500 g, 0.00332mol) was added, and the mixture was stirred for a further 1 hour. Themixture was quenched with brine and extracted with ethyl acetate. Theorganic phase was evaporated and the residue was purified by silica gelchromatography, eluting with 0 to 100% ethyl acetate in dichloromethane,to yield 1.17 g (92%) of the title compound. ¹H-NMR (300 MHz, CDCl₃, δ):8.40 (s, 1H), 7.29 (m, 5H), 7.00 (d, J=3.6 Hz, 1H), 6.33 (d, J=3.3 Hz,1H), 5.89 (dd, J=7.3 Hz, 15.3 Hz, 1H), 5.46 (ddd, J=4.3 Hz, 8.5 Hz, 18.1Hz, 1H), 4.48 (t, J=3.1 Hz, 1H), 3.79 (dd, J=7.2 Hz, 9.9 Hz, 1H), 3.60(dd, J=6.8 Hz, 9.9 Hz, 1H), 3.00 (m, 1H), 2.75 (dtd, J=4.0 Hz, 7.6 Hz,11.7 Hz, 1H), 2.45 (d, J=4.0 Hz, 1H), 2.22 (d, J=4.0 Hz, 3H), 1.96 (d,J=4.0 Hz, 2H), 0.90 (s, 18H), 0.08 (s, 12H).

Step b:((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol

7-[(1R,3S,4S)-3-[tert-butyl(dimethyl) silyl]oxy-4-([tert-butyl(dimethyl)silyl]-oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.66g, 0.00280 mol) was dissolved in a mixture of tetrahydrofuran (6.6 mL),water (6.6 mL, 0.36 mol), and acetic acid (19 mL, 0.34 mol). Thesolution was then heated to 40° C. overnight. The mixture was thencooled and evaporated, azeotroped with toluene (2×50 mL) and the residuewas purified by silica gel chromatography eluting with 0 to 100% ethylacetate in dichloromethane to yield the product as a white solid, 1.05 g(74%). LC/MS: R_(t)=1.68 min, ES⁺ 479 (AA standard).

Step c:(1R,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde

((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol(257.0 mg, 0.0005369 mol) was dissolved in methylene chloride (10.0 mL)under argon. N-Methylmorpholine N-oxide (126 mg, 0.00107 mol), and 4 Åmolecular sieves (250 mg, freshly flame dried) were then added and themixture was stirred for 10 minutes at room temperature.Tetrapropylammonium perruthenateVII (18.9 mg, 0.0000537 mol) was thenadded, and the resulting dark green solution was stirred for 1 h at roomtemperature. The reaction mixture was filtered through a silica gelplug, eluting with DCM (20 mL), followed by 50% ethyl acetate in DCM(150 mL). The eluate was evaporated to provide the product as a clearlight green oil. The residue was carried on to the next reaction withoutfurther purification.

Step d: Ethyl(E)-2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylenesulfonate

To a stirred solution of (diethoxy-phosphoryl)-methanesulfonic acidethyl ester (285 mg, 0.00110 mol) in tetrahydrofuran (5.0 mL) was added,dropwise, 2.5 M of n-butyllithium in hexane (440 μL, 0.00110 mol) at−78° C. under atmosphere of nitrogen. The mixture was then stirred for30 minutes. To this solution was added, dropwise, a solution of(1R,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde(212.0 mg, 0.0004447 mol) in tetrahydrofuran (5.0 mL) at −78° C. Theresulting pink solution was stirred for 1.5 h at −78° C. The reactionmixture was warmed and quenched by addition of saturated NH₄Cl (30 mL).The resultant mixture was extracted with DCM (3×30 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography with 30 to50% ethyl acetate in hexane to yield the product as a colorless oil, 132mg (51%). LC/MS: R_(t)=2.55 min, ES⁺ 583 (AA standard).

Step e: Ethyl2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonate

Ethyl-2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylenesulfonate(132.0 mg, 0.0002265 mol) was dissolved in ethanol (8.0 mL) and sodiumborohydride (42.8 mg, 0.00113 mol) was added. The reaction mixture wasstirred at room temperature overnight. The mixture was quenched withNH₄Cl solution, and the mixture was concentrated to remove the ethanol.The aqueous residue was then extracted with dichloromethane, and theorganic phase was concentrated. The residue was purified by silica gelchromatography 15% ethyl acetate in dichloromethane to yield theproduct, 92 mg (69%). LC/MS: R_(t)=2.51 min, ES⁺ 585 (AA standard).

Step f: N,N,N-tributylbutan-1-aminium2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonate

Ethyl2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonate(92 mg, 0.0001573 mol) and tetra-n-butylammonium iodide (62.0 mg,0.000168 mol) were dissolved in acetone (2.5 mL, 0.034 mol) and themixture was heated using microwave irradiation at 140° C. for 70seconds. The cooled reaction mixture was concentrated to dryness toyield the crude product, 140 mg. LC/MS: R_(t)=1.75 min, ES⁺ 557 (AAstandard).

Step g:2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonamide

N,N,N-tributylbutan-1-aminium2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonate(66.0 mg, 0.0000744 mol) was dissolved in methylene chloride (2.0 mL,0.031 mol) and N,N-dimethylformamide (5.50 μL, 0.0000710 mol) was added.The mixture was cooled to 0° C. and thionyl chloride (50.0 μL, 0.000685mol) was added dropwise. The reaction was allowed to stir at 0° C. for2.5 h. The reaction mixture was diluted with toluene and concentrated todryness. The residue was again azeotroped with toluene. The residue waseluted down a silica cartridge (˜3 g) with 0 to 10% THF/DCM to yield theacid chloride intermediate, 42 mg. The acid chloride was taken up in a0.500 M solution of ammonia in 1,4-dioxane (5.00 mL) and the resultantsolution was stirred overnight at room temperature under an atmosphereof nitrogen. The mixture was then evaporated and the residue waspartitioned between DCM and water. The organic phase was evaporated toyield the crude product, 35 mg (85%). LC/MS: R_(t)=1.64 min, ES⁺ 556 (AAstandard).

Step h: 2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide(Compound I-59)

2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonamide(32 mg, 0.000057 mol) was dissolved in tetrahydrofuran (1.0 mL, 0.012mol) and a 1.00 M solution of tetra-n-butylammonium fluoride intetrahydrofuran (0.100 mL) was added. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was quenched with a littlewater and then concentrated. Purification of the residue by silica gelchromatography, eluting with 0 to 100% of (9:1EtOAc:EtOH) in DCM,afforded the desired product, (9 mg, 40%). ¹H-NMR (400 MHz, MeOD, δ):8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H), 5.85 (t, J=7.7 Hz,1H), 5.43 (dddd, J=4.2 Hz, 8.4 Hz, 8.4 Hz, 8.4 Hz, 1H), 4.35 (t, J=3.7Hz, 1H), 3.13 (m, 3H), 2.91 (m, 1H), 2.63 (m, 1H), 2.49 (m, 1H), 2.35(ddd, J=1.2 Hz, 8.1 Hz, 13.8 Hz, 1H), 2.05 (m, 6H). LC/MS: R_(t)=1.07min, ES⁺ 442 (AA standard).

Example 64:(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide(Compound I-73) Step a: tert-Butyl{[(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)vinyl]sulfonyl}carbamate

tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate (602 mg, 1.45mmol) was dissolved in THF (50.0 mL) under an atmosphere of argon, a1.60 M solution of n-butyllithium in hexane (1.81 mL, 2.89 mmol) wasadded at −50° C., and the resultant mixture was stirred for 1 h. Asolution of(1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde(300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and theresulting mixture was stirred for 30 min at room temperature. Afterquenching by addition of water (200 mL), the mixture was extracted withEtOAc (100 mL×3). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography eluting with a gradient of 10 to 60% EtOAc in hexane toafford the title compound (84.0 mg, 21%). LC/MS: R_(t)=1.90 min, ES⁺654(FA standard).

Step b:(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylenesulfonamide

tert-Butyl{[(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)vinyl]sulfonyl}carbamate(120 mg, 0.17 mmol) was dissolved in DCM (10.0 mL) under an atmosphereof argon, and EtOH (0.05 mL, 8.72 mmol) was added at room temperature.To this mixture was added ZnBr₂ (0.10 mg, 0.44 mmol), and the resultingmixture was stirred for 4 h. After quenching by addition of water (20mL), the mixture was stirred for 1 h, and then was extracted with DCM(30 mL×3). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography, eluting with a gradient of 0 to 10% MeOH in DCM, toafford the title compound (91.8 mg, 90%). LC/MS: R_(t)=1.64 min, ES⁺ 554(FA standard).

Step c:(E)-2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide(Compound I-73)

(E)-2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylenesulfonamide(30 mg, 0.05 mmol) was dissolved in THF (2.00 mL). To this solution wasadded at room temperature a 1M solution of tetra-n-butylammoniumfluoride in THF (0.08 mL, 0.08 mmol), and the resulting mixture wasstirred for 1 h. The reaction mixture was quenched by the addition ofbrine (20 mL) and extracted with EtOAc (30 mL×3). The organic layer wasdried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified via silica gel chromatography, eluting with a gradient of 5 to15% MeOH in DCM, to afford the title compound (21.3 mg, 81%). ¹H NMR(CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.27-7.11 (m, 5H), 6.88 (dd, J=7.8,15.1 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.57 (dd, J=1.0, 15.1 Hz, 1H),5.85 (dd, J=7.7, 7.8 Hz, 1H), 5.47 (ddd, J=4.6, 8.6, 18.1 Hz, 1H),4.44-4.42 (m, 1H), 3.30-3.21 (m, 1H), 3.05 (ddd, J=3.4, 8.8, 15.8 Hz,1H), 2.96-2.83 (m, 1H), 2.66-2.58 (m, 1H), 2.44 (dt, J=10.0, 13.8 Hz,1H), 2.37 (ddd, J=1.8, 8.3, 13.8 Hz, 1H), 2.29 (ddd, J=4.6, 8.3, 13.8Hz, 1H), 2.10-1.92 (m, 2H) ppm. LC/MS: R_(t)=5.00 min, ES⁺ 440 (FA longpurity).

Example 65:N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide(Compound I-56) Step a: tert-butyl(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]carbamate

((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol(700.0 mg, 0.001462 mol), N-Boc-sulfonamide (398 mg, 0.00203 mol) andtriphenylphosphine (575 mg, 0.00219 mol) were dissolved in ethyl acetate(28 mL, 0.28 mol) at 50° C. under an atmosphere of nitrogen. Diethylazodicarboxylate (350.0 μL, 0.002223 mol) was added over 2-3 min and themixture was stirred at 50° C. for 30 minutes. The cooled mixture wasevaporated and the residue purified by silica gel chromatography,eluting with 10 to 100% ethyl acetate in hexanes, to yield the productas a white solid, 636 mg (66%). LC/MS: R_(t)=2.55 min, ES⁺ 657 (AAstandard).

Step b: tert-butyl(aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl-2-hydroxycyclopentyl)methyl]carbamate

tert-Butyl (aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)-methyl]carbamate(457 mg, 0.000696 mol) was dissolved in tetrahydrofuran (10.0 mL), 1.00M aqueous hydrochloric acid (10.0 mL), and ethanol (10.0 mL). Themixture was stirred at room temperature overnight. Sodium bicarbonate(842 mg, 0.0100 mol) was added to the mixture, followed by water (10mL). The mixture was then concentrated to ˜20 mL volume, and thisaqueous residue was extracted with EtOAc (2×50 mL). The separatedorganics were concentrated in vacuo and the residue was purified bysilica gel chromatography, eluting with 100% ethyl acetate to yield theproduct, 362 mg (96%). LC/MS: R_(t)=1.77 min, ES' 543 (AA standard).

Step c:N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide(Compound I-56)

tert-Butyl (aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]carbamate(345 mg, 0.000636 mol) was dissolved in 2:1 methylenechloride:trifluoroacetic acid (20 mL:10 mL) and left to stand for 15minutes at room temperature. The mixture was diluted with toluene (30mL) and evaporated to dryness. The residue was then re-subjected to thesame conditions and azeotroped with toluene after completion. Theresidue was purified by silica gel chromatography, eluting with 5 to 10%Methanol in dichloromethane, to yield the product, 135 mg (48%). ¹H-NMR(400 MHz, MeOD) δ 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H),5.85 (t, J=7.8 Hz, 1H) 5.43 (ddd, J=4.6 Hz, 8.5 Hz, 17.8 Hz, 1H), 4.46(t, J=3.6 Hz, 1H), 3.15 (dd, J=7.1 Hz, 12.9 Hz, 1H), 3.05 (ddd, J=3.3Hz, 8.7 Hz, 15.4 Hz, 1H), 2.91 (m, 1H), 2.63 (m, 1H), 2.33 (ddd, J=1.5Hz, 8.0 Hz, 13.8 Hz, 1H), 2.20 (m, 2H), 2.02 (m, 2H). LC/MS: R_(t)=1.45min, ES⁺ 443 (AA standard).

Example 66:N-{[(1S,2S,4R)-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methyl}sulfamide(Compound I-74)

The title compound was prepared following the procedures described inExample 64a-b and Example 66a-c starting from(1S,2S,4R)-4-{4-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol(Example 41). 1H-NMR (300 MHz, MeOD) δ 8.20 (s, 1H), 7.21 (m, 5H), 6.66(d, J=3.6 Hz, 1H) 5.92 (d, J=5.3 Hz, 1H) 5.43 (m, 1H), 4.47 (t, J=3.5Hz, 1H), 4.30 (dt, J=2.8 Hz, 5.2 Hz, 1H), 3.35 (s, 3H), 3.15 (m, 3H),2.64 (m, 1H), 2.27 (m, 3H), 2.03 (ddd, J=4.7 Hz, 9.0 Hz, 13.6 Hz, 1H).

LC/MS: R_(t)=6.88 min, ES⁺ 473 (AA purity).

Example 67:N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide(Compound I-75) Step a:N-[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]-N-methylsulfamide

tert-Butyl(aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]-carbamate(108 mg, 0.000164 mol) was dissolved in tetrahydrofuran (2.0 mL) underan atmosphere of nitrogen. Lithium tetrahydroaluminate (12.5 mg,0.000329 mol) was added and the mixture heated at 50° C. for 80 minutes.The reaction was then cooled, quenched with water and acidified to ˜pH 6with 1M HCl. This mixture was then extracted with ethyl acetate, theseparated organic phase was evaporated, and the residue was purified bysilica gel chromatography, eluting with 10 to 100% ethyl acetate inhexanes, to yield the product, 25 mg (27%). LC/MS: R_(t)=2.34 min, ES⁺571 (AA standard).

Step b:N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]-N-methylsulfamide(Compound I-75)

N-[((1S,2S,4R)-2-[tert-Butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]-N-methylsulfamide(25.0 mg, 0.0000438 mol) was dissolved in tetrahydrofuran (2.0 mL),ethanol (2.0 mL) and 1.00 M of hydrochloric acid in water (2.0 mL). Themixture was stirred overnight at room temperature. The solution wasevaporated to dryness, and the residue was dissolved in methanol andtreated with a 7.00 M solution of ammonia in methanol (0.1 mL). Solventswere again evaporated, and the residue was purified by silica gelchromatography, eluting with 2 to 10% methanol in dichloromethane toyield the product, 9.8 mg (49%). ¹H-NMR (400 MHz, MeOD) δ 8.16 (s, 1H),7.19 (m, 5H), 6.62 (d, 1H, J=3.6 Hz), 5.84 (t, J=7.7 Hz, 1H), 5.43 (ddd,J=4.5 Hz, 8.6 Hz, 12.8 Hz, 1H), 4.43 (t, J=3.7 Hz, 1H), 3.25 (dd, J=8.1Hz, 13.7 Hz, 1H), 3.14 (dd, J=7.2 Hz, 13.7 Hz, 1H), 3.05 (ddd, J=3.3 Hz,8.8 Hz, 15.8 Hz, 1H), 2.91 (m, 1H), 2.74 (m, 1H), 2.63 (m, 1H), 2.34(ddd, J=1.1 Hz, 7.8 Hz, 13.6 Hz, 1H), 2.20 (m, 2H), 1.99 (m, 2H).

LC/MS: R_(t)=1.51 min, ES⁺ 457 (AA standard).

Example 68:((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylmethanesulfonate (Compound I-76) Step a:((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylmethanesulfonate

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol(0.345 g, 0.721 mmol) was dissolved in methylene chloride (5.00 mL, 78.0mmol) under an atmosphere of argon. Triethylamine (0.251 mL, 1.80 mmol)was added, and the solution was cooled to 0° C. Methanesulfonyl chloride(0.0669 mL, 0.865 mmol) was added in one portion. The solution wasstirred at 0° C. under an atmosphere of argon for 30 minutes. Thesolution was diluted with EtOAc, washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to givethe title compound (0.415 g, 89%). LC/MS: R_(t)=2.45 min, ES⁺ 557 (AAstandard).

Step b:((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetonitrile

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylmethanesulfonate (0.415 g, 0.641 mmol) was dissolved in dimethylsulfoxide (7.00 mL, 98.6 mmol) under an atmosphere of argon. Sodiumcyanide (0.166 g, 3.28 mmol) was added, and the mixture was stirred at60° C. for 24 h. The reaction mixture was heated for an additional 24 hat 70° C. The reaction mixture was cooled to ambient temperature,diluted with EtOAc, washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified via silica gel chromatography, eluting with a gradient of 0 to40% EtOAc in methylene chloride, to afford the title compound (0.306 g,98%). LC/MS: R_(t)=1.85 min, ES⁺ 488. (FA standard).

Step c.((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetaldehyde

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetonitrile(0.150 g, 0.308 mmol) was dissolved in methylene chloride under anatmosphere of argon and cooled to −78° C. Diisobutylaluminum hydride(1.0M in methylene chloride, 0.340 mL, 0.340 mmol) was added to thesolution and the reaction mixture was stirred for 30 minutes at −78° C.After a second addition of diisobutylaluminum hydride (1.0 M inmethylene chloride, 0.340 mL, 0.340 mmol), the solution was stirred foran additional 30 minutes at −78° C. A third addition ofdiisobutylaluminum hydride (1.0 M in methylene chloride, 0.340 mL, 0.340mmol) was made, and the solution was stirred for another 30 minutes at−78° C. The reaction was quenched with a saturated solution of sodiumpotassium tartrate tetrahydrate. EtOAc was added and the mixture wasstirred until the layers were clear. The layers were separated. Theaqueous layer was extracted with diethyl ether. The combined organicextracts were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound (0.160 g,100%). LC/MS: R_(t)=1.80 min, ES⁺ 491 (FA standard).

Step d:2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyly]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanol

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetaldehyde(0.164 g, 0.314 mmol) was dissolved in methanol (5.00 mL, 123 mmol)under an atmosphere of argon and cooled to 0° C. Sodium tetrahydroborate(0.0291 g, 0.754 mmol) was added and the reaction was stirred for 10minutes. Additional sodium tetrahydroborate (0.0143 g, 0.377 mmol) wasadded, and the reaction mixture was stirred for another 30 minutes. Thereaction was quenched with water, extracted with EtOAc, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography, eluting with agradient of 0 to 100% EtOAc in methylene chloride, to afford the titlecompound (0.0694 g, 45%). LC/MS: R_(t)=1.65 min, ES⁺ 494 (FA standard).

Step e:2-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylsulfamate

((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanol(0.0694 g, 0.141 mmol) was dissolved in acetonitrile (3.00 mL, 57.4mmol) and methylene chloride (2.00 mL, 31.2 mmol) under an atmosphere ofargon. Triethylamine (0.0589 mL, 0.422 mmol) was added, and the solutionwas cooled to 0° C. Chlorosulfonamide (2.00M in acetonitrile, 0.141 mL)was added and the solution was immediately warmed to room temperature.After 30 minutes, additional chlorosulfonamide (2.00M in acetonitrile,0.141 mL) and triethylamine (0.0589 mL, 0.422 mmol) were added and thereaction was stirred for 30 minutes. The reaction was quenched withmethanol and a 1:1 solution of saturated sodium bicarbonate and water.The mixture was extracted with EtOAc. The combined organic extracts werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography, eluting with 0 to 50% EtOAc in methylene chloride, togive the title compound (0.0805 g, 55%). LC/MS: R_(t)=1.70 min, ES⁺ 573(FA standard).

Step f:2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylsulfamate (Compound I-76)

2-((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethylsulfamate (0.0442 g, 0.0773 mmol) was dissolved in pyridine (0.344 mL,4.25 mmol) and tetrahydrofuran (0.345 mL, 4.25 mmol). The solution wascooled to 0° C. Pyridine hydrofluoride (0.500 mL, 5.55 mmol) was addeddropwise. The solution was warmed to room temperature. After one hour,pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. After two hours,pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. The solution wasstirred for 24 h. The reaction was quenched with dropwise addition ofsaturated sodium bicarbonate, and the mixture was extracted with EtOAc.The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography, eluting with 0 to 5% MeOH in EtOAc, to give thetitle compound (0.005 g, 0.01 mmol). ¹H NMR (CD₃OD, 400 MHz, δ): 8.17(s, 1H), 7.28-7.12 (m, 5H) 6.67 (d, J=3.61 Hz 1H) 5.58 (t, J=7.44, 7.44Hz 1H), 5.48-5.40 (m, 1H), 4.40-4.35 (m, 1H), 4.28-4.17 (m, 2H),3.10-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.68-2.47 (m, 1H), 2.57-2.47 (m,1H), 2.38-1.98 (m, 5H), 1.89-1.80 (m, 1H) ppm. LC/MS: R_(t)=1.25 min,ES⁺ 458 (FA standard).

Example 70: Diastereoisomeric mixture of(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentylsulfamate and(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3d]-pyrimidin-7-yl}-2-hydroxycyclopentylsulfamate (Compounds I-77 and I-78)

Step a: Cyclopent-3-en-1-yl methanesulfonate

3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL).Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) andmethanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and thereaction mixture was stirred at 35° C. for 4 h.N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonylchloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirredovernight. TLC indicated complete conversion. The reaction mixture wascooled and concentrated. The residue was purified by silica gelchromatography, eluting with DCM, to afford the title compound as aclear oil (0.660 g, 68%).

Step b:7-Cyclopent-3-en-1-yl-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]-pyrimidin-4-amine

N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(1.32 g, 5.29 mmol) was azeotroped with toluene and placed under highvacuum for 30 min. N,N-Dimethylformamide (17.7 mL) was added, followedby cesium carbonate (1.99 g, 6.10 mmol). The mixture was stirred at 70°C. for 10 min. Cyclopent-3-en-1-yl methanesulfonate (0.660 g, 4.07 mmol)in N,N-dimethylformamide (12.6 mL) was added dropwise. The reactionmixture was heated to 110° C. for 1 h. The reaction mixture was cooled,quenched with brine and diluted with H₂O. The aqueous layer wasextracted with EtOAc (3×), washed with H₂O and brine, dried (Na₂SO₄),filtered, and concentrated. The residue was purified by via silica gelchromatography, eluting with a gradient of 0 to 5% MeOH in DCM followedby 25 to 50% EtOAc in hexanes, to afford the title compound as a palebrown solid (0.684 g, 53%). LC/MS: R_(t)=1.38 min, ES⁺ 317 (FAstandard).

Step c:(1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol

7-Cyclopent-3-en-1-yl-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(0.312 g, 0.986 mmol) was stirred in tert-butyl alcohol (4.9 mL) and H₂O(4.9 mL). AD-mix-α (Sigma-Aldrich, 1.4 g) was added, and the suspensionwas stirred at rt overnight. TLC indicated complete conversion. Thereaction was quenched with sodium sulfite (1.48 g, 11.7 mmol), and themixture was stirred for 5 h. The reaction mixture was diluted with EtOAcand H₂O, and the aqueous layer was extracted with EtOAc (2×). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified via silica gel chromatography, eluting with EtOAc,to afford the title compound as a white solid (0.190 g, 55%).

Step d: Diastereoisomeric mixture of(1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentylsulfamate and (1R,2S,4S)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentylsulfamate (Compounds I-77 and I-78)

(1R,2S,4S)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol(0.080 g, 0.23 mmol) was azeotroped with toluene and then was dissolvedin anhydrous acetonitrile (2.3 mL). Pyridine (0.0369 mL, 0.458 mmol) wasadded. The reaction mixture was cooled to 0° C., and a 2N solution ofchlorosulfonamide in acetonitrile (0.144 mL) was added dropwise. Thereaction was stirred for 1 h, and then additional 2N chlorosulfonamidein acetonitrile (0.028 mL) was added. After 30 min, additional 2Nchlorosulfonamide in acetonitrile (0.0342 mL) was added, and thereaction mixture was stirred for 2 h. The reaction was quenched withmethanol, and the mixture was concentrated in vacuo. The residue waspurified by preparative thin layer chromatography using DCM:AcCN:MeOH(50:45:5). The relevant band was cut, washed with acetone, filtered, andconcentrated to give a mixture of diastereomers as a white solid. (11mg, 11%). ¹H NMR (CDCl₃, 400 NMR, δ): 8.36-8.27 (m, 1H); 7.38-7.09 (m,5H); 6.90-6.80 (m, 1H); 6.36-6.20 (m, 1H); 5.95-5.76 (m, 1H); 5.51-5.22(m, 2H); 4.83-4.68 (m, 1H); 3.87-3.72 (m, 1H); 3.12-2.83 (m, 2H);2.75-2.53 (m, 1H); 2.50-2.14 (m, 2H); 2.08-1.79 (m, 2H) ppm. LC/MS:R_(t)=1.16 min, ES⁺ 430 (FA standard).

The following additional compounds of formula (I) were also prepared:

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-(methoxymethyl)-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-79)

¹H NMR (CD₃OD, 400 MHz, δ): 8.20 (s, 1H), 7.32-7.16 (m, 5H), 6.64 (d,J=3.6 Hz, 1H), 5.97 (d, J=7.0 Hz, 1H), 5.50-5.41 (m, 1H), 4.51-4.46 (m,1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H),3.53-3.40 (m, 1H), 3.41-3.35 (m, 1H), 3.18 (s, 3H), 3.11-2.95 (m, 3H),2.84-2.75 (m, 1H), 2.33 (ddd, J=1.4, 7.7, 13.5 Hz, 1H), 2.29-2.19 (m,2H), 2.04 (ddd, J=4.9, 9.5, 14.2 Hz, 1H) ppm. LC/MS: R_(t)=11.24 min,ES⁺ 488 (FA long purity).

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-(methoxymethyl)-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-80)

¹H NMR (CD₃OD, 400 MHz, δ): 8.20 (s, 1H), 7.32-7.16 (m, 5H), 6.64 (d,J=3.6 Hz, 1H), 5.97 (d, J=7.0 Hz, 1H), 5.50-5.41 (m, 1H), 4.51-4.46 (m,1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (dd, J=7.3, 9.8 Hz, 1H),3.53-3.40 (m, 1H), 3.41-3.35 (m, 1H), 3.18 (s, 3H), 3.11-2.95 (m, 3H),2.84-2.75 (m, 1H), 2.33 (ddd, J=1.4, 7.7, 13.5 Hz, 1H), 2.29-2.19 (m,2H), 2.04 (ddd, J=4.9, 9.5, 14.2 Hz, 1H) ppm. LC/MS: R_(t)=11.24 min,ES⁺ 488 (FA long purity).

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-81)

¹H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.32-7.16 (m, 5H), 6.69 (d,J=3.6 Hz, 1H), 5.86 (d, J=7.2 Hz, 1H), 5.50-5.41 (m, 1H), 4.51-4.47 (m,1H), 4.38 (dd, J=9.7, 7.6 Hz, 1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H),3.14-3.08 (m, 1H), 2.95-2.88 (m, 1H), 2.83-2.72 (m, 2H), 2.37-2.20 (m,3H), 2.09-2.00 (m, 1H), 0.98 (d, J=7.1 Hz, 3H) ppm. LC/MS: R_(t)=7.93min, ES⁺ 458 (AA long purity).

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-82)

¹H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.32-7.16 (m, 5H), 6.69 (d,J=3.6 Hz, 1H), 5.86 (d, J=7.2 Hz, 1H), 5.50-5.41 (m, 1H), 4.51-4.47 (m,1H), 4.38 (dd, J=9.7, 7.6 Hz, 1H), 4.20 (dd, J=7.4, 9.7 Hz, 1H),3.14-3.08 (m, 1H), 2.95-2.88 (m, 1H), 2.83-2.72 (m, 2H), 2.37-2.20 (m,3H), 2.09-2.00 (m, 1H), 0.98 (d, J=7.1 Hz, 3H) ppm. LC/MS: R_(t)=7.93min, ES⁺ 458 (AA long purity).

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1R,2R)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-83)

¹H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.31-7.15 (m, 5H), 6.66 (d,J=3.60 Hz, 1H), 5.94 (d, J=7.28 Hz, 1H), 5.48-5.41 (m, 1H), 4.48 (dd,J=3.98, 3.03 Hz, 1H), 4.36 (dd, J=9.74, 7.58 Hz, 1H), 4.19 (dd, J=9.73,7.33 Hz, 1H), 3.07-3.01 (m, 1H), 2.91-2.76 (m, 2H), 2.65-2.54 (m, 1H),2.38-2.19 (m, 3H), 2.03 (ddd, J 13.95, 9.17, 4.93 Hz, 1H), 1.59 (ddd,J=13.33, 7.40, 5.81 Hz, 1H), 1.38-1.28 (m, 1H), 0.93 (t, J=7.41 Hz, 3H)ppm. LC/MS: R_(t)=8.36 min, ES⁺ 472 (AA long purity).

[(1R,2R,4S)-2-hydroxy-4-(4-{[(1S,2S)-2-ethyl-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate(Compound I-84)

¹H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.31-7.15 (m, 5H), 6.66 (d,J=3.60 Hz, 1H), 5.94 (d, J=7.28 Hz, 1H), 5.48-5.41 (m, 1H), 4.48 (dd,J=3.98, 3.03 Hz, 1H), 4.36 (dd, J=9.74, 7.58 Hz, 1H), 4.19 (dd, J=9.73,7.33 Hz, 1H), 3.07-3.01 (m, 1H), 2.91-2.76 (m, 2H), 2.65-2.54 (m, 1H),2.38-2.19 (m, 3H), 2.03 (ddd, J=13.95, 9.17, 4.93 Hz, 1H), 1.59 (ddd,J=13.33, 7.40, 5.81 Hz, 1H), 1.38-1.28 (m, 1H), 0.93 (t, J=7.41 Hz, 3H)ppm. LC/MS: R_(t)=8.36 min, ES⁺ 472 (AA long purity).

((1S,2S,4R)-2-hydroxy-4-(4-((1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methylsulfamate (Compound I-85)

¹H NMR (CD₃OD, 400 MHz, δ): 8.17 (s, 1H), 7.25 (d, J=7.4, 1H), 7.20 (d,J=3.6 Hz, 1H), 7.15-7.06 (m, 3H), 6.66 (d, J=3.6 Hz, 1H), 5.81 (m, 1H),5.50-5.40 (m, 1H), 4.49 (m, 1H), 4.37 (dd, J=3.3, 7.0 Hz, 1H), 4.20 (dd,J=7.3, 9.7 Hz, 1H), 3.85-3.82 (m, 1H), 3.42 (s, 3H), 3.06-2.96 (m, 1H),2.84-2.73 (m, 2H), 2.38-2.18 (m, 4H), 2.08-2.18 (m, 2H) ppm. LC/MS:R_(t)=1.51 min, ES⁺ 488 (AA standard).

((1S,2S,4R)-4-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methoxycyclopentyl)methylsulfamate (Compound I-86)

¹H NMR (CD₃OD, 400 MHz, δ): 8.13 (s, 1H), 7.23-7.08 (m, 5H), 6.60 (d,J=3.6 Hz, 1H), 5.81 (t, J=7.69, 15.4 Hz, 1H), 5.36-5.25 (m, 1H), 4.32(dd, J=7.5, 9.6 Hz, 1H), 4.13 (dd, J=7.3, 9.6 Hz, 1H), 4.02-4.00 (m,1H), 3.32 (s, 3H), 3.06-2.98 (m, 1H), 2.94-2.77 (m, 2H), 2.63-2.54 (m,1H), 2.54-2.48 (m, 1H), 2.18-2.08 (m, 2H) ppm. LC/MS: R_(t)=8.10 min,ES⁺ 458 (AA standard).

Example 69: Enzyme Preparation

All protein accession numbers provided herein refer to the EntrezProtein database maintained by the National Center for BiotechnologyInformation (NCBI), Bethesda, Md.

Generation of E1 Enzymes

Following manufacturer instructions, baculoviruses were generated withthe Bac-to-Bac Expression System (Invitrogen) for the followingproteins: untagged NAEα (APPBP1; NP_003896.1), N-terminally His-taggedNAEβ (UBE1C; NP_003959.3), untagged SAEα (SAE1; NP_005491.1),N-terminally His-tagged SAEβ (UBA2; NP_005490.1), N-terminallyHis-tagged murine UAE (UBE1X; NP_033483). NAEα/His-NAEβ andSAEα/His-SAEβ complexes were generated by co-infection of Sf9 cells,which were harvested after 48 hours. His-mUAE was generated by singleinfection of Sf9 cells and harvested after 72 hours. Expressed proteinswere purified by affinity chromatography (Ni-NTA agarose, Qiagen) usingstandard buffers.

Generation of E2 Enzymes

Ubc12 (UBE2M; NP_003960.1), Ubc9 (UBE2I; NP_003336.1), Ubc2 (UBE2A;NP_003327.2) were subcloned into pGEX (Pharmacia) and expressed asN-terminally GST tagged fusion proteins in E. coli. Expressed proteinswere purified by conventional affinity chromatography using standardbuffers.

Generation of Ubl Proteins

Nedd8 (NP 006147), Sumo-1 (NP_003343) and Ubiquitin (with optimizedcodons) were subcloned into pFLAG-2 (Sigma) and expressed asN-terminally Flag tagged fusion proteins in E. coli. Expressed proteinswere purified by conventional chromatography using standard buffers.

Example 70: E1 Enzyme Assays Nedd8-Activating Enzyme (NAE) HTRF Assay.

The NAE enzymatic reaction totaled 50 μL and contained 50 mM HEPES (pH7.5), 0.05% BSA, 5 mM MgCl₂, 20 μM ATP, 250 μM GSH, 0.01 μM Ubc12-GST,0.075 μM Nedd8-Flag and 0.28 nM recombinant human NAE enzyme. Theenzymatic reaction mixture, with and without compound inhibitor, wasincubated at 24° C. for 90 minutes in a 384-well plate beforetermination with 25 μL of Stop/Detection buffer (0.1M HEPES pH 7.5,0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptate labeledmonoclonal anti-FLAG M2 antibody (CisBio International) and 8.125 μg/mLPHYCOLINK goat anti-GST allophycocyanin (XL-APC) antibody (Prozyme)).After incubation for 3 hours at 24° C., quantification of the FRET wasperformed on the Analyst™ HT 96.384 (Molecular Devices).

Compounds I-1 to I-54, I-56, I-59, I-61 to I-76, and I-79 to I-85exhibited IC₅₀ values less than or equal to 10 μM in this assay.Compounds I-1, I-2, I-3, I-4, I-6, I-7, I-8, I-12, I-13, I-14, I-15,I-16, I-17, I-18, I-19, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28,I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40,I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52,I-54, I-56, I-59, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69,I-70, I-71, I-72, I-73, I-74, I-76, I-78, I-79, I-80, I-81, I-82, I-83,I-84, and I-85 exhibited IC₅₀ values less than or equal to 100 nM inthis assay.

Sumo-Activating Enzyme (SAE) HTRF Assay.

The SAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.01 μM Ubc9-GSTand 0.125 μM Sumo-Flag respectively and the concentration of ATP was 0.5μM. Recombinant human SAE (0.11 nM) was the source of enzyme.

Ubiquitin-Activating Enzyme (UAE) HTRF Assay.

The UAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.005 μM Ubc2-GSTand 0.125 μM Ubiquitin-Flag respectively and the concentration of ATPwas 0.1 M. Recombinant mouse UAE (0.3 nM) was the source of enzyme.

Example 71: Cellular Assays

Selected compounds of formula (I) were tested in cellular assays:

Anti-Proliferation Assay (WST)

Calu-6 (2400/well) or other tumor cells in 80 μL of appropriate cellculture medium (MEM for Calu6, Invitrogen) supplemented with 10% fetalbovine serum (Invitrogen) was seeded in wells of a 96-well cell cultureplate and incubated for 24 hours in a tissue culture incubator. Compoundinhibitors were added in 20 μL culture media to the wells and the plateswas incubated for 72 hours at 37° C. 10% final concentration of WST-1reagent (Roche) was added to each well and incubated for 3.5 hours (forCalu6) at 37° C. The optical density for each well was read at 450 nmusing a spectrophotometer (Molecular Devices). Percent inhibition wascalculated using the values from a DMSO control set to 100% viability.

Anti-Proliferation Assay (ATPLite)

Calu-6 (1500 cells/well) or other tumor cells were seeded in 72 μL ofappropriate cell culture medium (MEM for Calu6, Invitrogen) supplementedwith 10% fetal bovine serum (Invitrogen) in wells of a 384-wellPoly-D-Lysine coated cell culture plate. Compound inhibitors were addedin 8 μL 10% DMSO/PBS to the wells and the plates were incubated for 72hours at 37° C. Cell culture medium was aspirated, leaving 25 μL in eachwell. 25 μL of ATPlite 1step™ reagent (Perkin Elmer) was added to eachwell. The luminescence for each well was read using the LeadSeekerMicroplate Reader (Molecular Devices). Percent inhibition was calculatedusing the values from a DMSO control set to 100% viability.

Example 72: In Vivo Assays

Selected compounds of formula (I) were tested in in vivo assays.

In Vivo Tumor Efficacy Model

Calu6 (5×10⁶ cells), HCT116 (2×10⁶ cells) or other tumor cells in 100 μLphosphate buffered saline were aseptically injected into thesubcutaneous space in the right dorsal flank of female Ncr nude mice(age 5-8 weeks, Charles River) using a 26-gauge needle. Beginning on day7 after inoculation, tumors were measured twice weekly using a verniercaliper. Tumor volumes were calculated using standard procedures(0.5×(length×width²)). When the tumors reached a volume of approximately200 mm³ mice were randomized into groups and injected intravenously inthe tail vein with compound inhibitor (100 μL) at various doses andschedules. Alternatively, compound inhibitor may be delivered to mice byintraperitoneal or subcutaneous injection or oral administration. Allcontrol groups received vehicle alone. Tumor size and body weight wasmeasured twice a week and the study terminated when the control tumorsreached approximately 2000 mm³.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

While a number of embodiments of this invention have been described, itis apparent that the provided basic examples may be altered to conveyother embodiments, which utilize the compounds and methods of thisinvention. It will thus be appreciated that the scope of this inventionhas been represented herein by way of example and is not intended to belimited by the specific embodiments, rather is defined by the appendedclaims.

1. A compound of formula (I):

 or a pharmaceutically acceptable salt thereof, wherein: stereochemicalconfigurations depicted at asterisked positions indicate relativestereochemistry; Ring A is selected from the group consisting of:

 wherein one ring nitrogen atom in Ring A optionally is oxidized; X is—C(R^(f1))₂, —N(R^(f2))—, or —O—; Y is —O—, —S—, or —C(R^(m))(R^(n))—;R^(a) is selected from the group consisting of hydrogen, fluoro, —CN,—N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵,—OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(a) andR^(b) together form ═O; or R^(a) and R^(c) together form a bond; R^(b)is selected from the group consisting of hydrogen, fluoro, C₁₋₄aliphatic, and C₁₋₄ fluoroaliphatic; or R^(b) and R^(a) together form═O; or R^(b), taken together with R^(d) and the intervening carbonatoms, forms a fused cyclopropane ring, which is optionally substitutedwith one or two substituents independently selected from fluoro or C₁₋₄aliphatic; or R^(b), taken together with R^(e) and the interveningcarbon atoms, forms a fused cyclopropane ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic; R^(c) is selected from the group consisting ofhydrogen, fluoro, —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵,—C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with one or twosubstituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); orR^(a) and R^(c) together form a bond; or R^(c) and R^(d) together form═O; R^(d) is selected from the group consisting of hydrogen, fluoro,C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; or R^(d) and R^(c) togetherform ═O; or R^(d), taken together with R^(b) and the intervening carbonatoms, forms a fused cyclopropane ring, which is optionally substitutedwith one or two substituents independently selected from fluoro or C₁₋₄aliphatic; or R^(d), taken together with R^(e′) and the interveningcarbon atoms, forms a fused cyclopropane ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic; R^(e) is hydrogen, or C₁₋₄ aliphatic; orR^(e), taken together with one R^(f) and the intervening carbon atoms,forms a 3- to 6-membered spirocyclic ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic; or R^(e), taken together with R^(m) and theintervening carbon atoms, forms a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; or R^(e), taken together withR^(b) and the intervening carbon atoms, forms a fused cyclopropane ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; R^(e′) is hydrogenor C₁₋₄ aliphatic; or R^(e′), taken together with R^(m) and theintervening carbon atoms, forms a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; or R^(e′), taken together withR^(d) and the intervening carbon atoms, forms a fused cyclopropane ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; each R^(f) isindependently hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic,provided that if X is —O— or —NH—, then R^(f) is not fluoro; or twoR^(f) taken together form ═O; or two R^(f), taken together with thecarbon atom to which they are attached, form a 3- to 6-memberedcarbocyclic ring; or one R^(f), taken together with R^(e) and theintervening carbon atoms, forms a 3- to 6-membered spirocyclic ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; or one R^(f),taken together with an adjacent R^(f1) and the intervening carbon atoms,forms a cyclopropyl ring, which is optionally substituted with one ortwo substituents independently selected from fluoro or C₁₋₄ aliphatic;or one R^(f) and one R^(f1) together form a double bond; each R^(f1) isindependently hydrogen or fluoro; or one R^(f1), taken together with anadjacent R^(f) and the intervening carbon atoms forms a cyclopropylring, which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; or one R^(f1) andone R^(f) together form a double bond; R^(f2) is hydrogen, C₁₋₄aliphatic, or C₁₋₄ fluoroaliphatic; R^(g) is hydrogen, halo, —NO₂, —CN,—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵,—C(R⁶)═N—OR⁵, or an optionally substituted aliphatic, aryl, heteroaryl,or heterocyclyl; each R^(h) independently is hydrogen, halo, —CN—, —OR⁵,—N(R⁴)₂, —SR⁶, or an optionally substituted C₁₋₄ aliphatic group; R ishydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally substituted aliphatic,aryl, or heteroaryl group; R^(k) is hydrogen, halo, —OR⁵, —SR⁶, —N(R⁴)₂,or an optionally substituted C₁₋₄ aliphatic group; R^(m) is hydrogen,fluoro, —N(R⁴)₂, or an optionally substituted C₁₋₄ aliphatic group; orR^(m) and R^(n) together form ═O or ═C(R⁵)₂; or R^(m) and R^(e), takentogether with the intervening carbon atoms, form a fused cyclopropanering, which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; or R^(m) andR^(e′), taken together with the intervening carbon atoms, form a fusedcyclopropane ring, which is optionally substituted with one or twosubstituents independently selected from fluoro or C₁₋₄ aliphatic; R^(n)is hydrogen, fluoro, or an optionally substituted C₁₋₄ aliphatic group;or R^(m) and R^(n) together form ═O or ═C(R⁵)₂; each R⁴ independently ishydrogen or an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; or two R⁴ on the same nitrogen atom, taken togetherwith the nitrogen atom, form an optionally substituted 4- to 8-memberedheterocyclyl ring having, in addition to the nitrogen atom, 0-2 ringheteroatoms independently selected from N, O, and S; R^(4x) is hydrogen,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portionof which may be optionally substituted; R^(4y) is hydrogen, C₁₋₄ alkyl,C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted, or an optionally substituted 5- or 6-memberedaryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y), takentogether with the nitrogen atom to which they are attached, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R⁵ independently is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀ar(C₁₋₄)alkyl; each R⁶ independently is an optionally substitutedaliphatic, aryl, or heteroaryl group; and m is 0, 1, 2, or 3, providedthat Y is —C(R^(m))(R^(n))— when m is
 0. 2. A compound of formula (I-A):

 or a pharmaceutically acceptable salt thereof, wherein: stereochemicalconfigurations depicted at asterisked positions indicate relativestereochemistry; Ring A is selected from the group consisting of:

 wherein one ring nitrogen atom in Ring A optionally is oxidized; X is—CH₂—, —CHF—, —CF₂—, —NH—, or —O—; Y is —O—, —S—, or —C(R^(m))(R^(n))—;R^(a) is selected from the group consisting of hydrogen, fluoro, —CN,—N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵,—OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(a) andR^(c) together form a bond; R^(b) is selected from the group consistingof hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; R^(c) isselected from the group consisting of hydrogen, fluoro, —CN, —N₃, —OR⁵,—N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂,—OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with one or two substituents independentlyselected from the group consisting of —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c) together forma bond; R^(d) is selected from the group consisting of hydrogen, fluoro,C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; R^(e) is hydrogen, or C₁₋₄aliphatic; or R^(e), taken together with one R^(f) and the interveningcarbon atoms, forms a 3- to 6-membered spirocyclic ring; R^(e′) ishydrogen or C₁₋₄ aliphatic; each R^(f) is independently hydrogen,fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic, provided that if X is—O— or —NH—, then R^(f) is not fluoro; or two R^(f) taken together form═O; or two R^(f), taken together with the carbon atom to which they areattached, form a 3- to 6-membered carbocyclic ring; or one R^(f), takentogether with R^(e) and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; R^(g) is hydrogen, halo, —NO₂, —CN,—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵,—C(R⁶)═N—OR⁵, or an optionally substituted aliphatic, aryl, heteroaryl,or heterocyclyl; each R^(h) independently is hydrogen, halo, —CN—, —OR⁵,—N(R⁴)₂, —SR⁶, or an optionally substituted C₁₋₄ aliphatic group; R^(j)is hydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally substitutedaliphatic, aryl, or heteroaryl group; R^(k) is hydrogen, halo, —OR⁵,—SR⁶, —N(R⁴)₂, or an optionally substituted C₁₋₄ aliphatic group; R^(m)is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted C₁₋₄aliphatic group; and R^(n) is hydrogen, fluoro, or an optionallysubstituted C₁₋₄ aliphatic group; or R^(m) and R^(n) together form ═O or═C(R⁵)₂; each R⁴ independently is hydrogen or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on thesame nitrogen atom, taken together with the nitrogen atom, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted; R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted, or an optionally substituted 5- or 6-memberedaryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y), takentogether with the nitrogen atom to which they are attached, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R⁵ independently is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀ar(C₁₋₄)alkyl; each R⁶ independently is an optionally substitutedaliphatic, aryl, or heteroaryl group; and m is 1, 2, or
 3. 3. (canceled)4. The compound of claim 2, characterized by one or more of thefollowing features: (a) X is —O—; (b) Y is —O— or —CH₂—; (c) R^(a) is—OH; (d) R^(b) and R^(d) are each independently hydrogen, fluoro, orC₁₋₄ aliphatic; (e) R^(c) is hydrogen, fluoro, or —OR⁵; (f) R^(e) andR^(e′) are each hydrogen; (g) each R^(f) is hydrogen; (h) each R^(h) ishydrogen; (i) R is hydrogen or C₁₋₄ aliphatic; (j) R^(k) is hydrogen,halo, or C₁₋₄ aliphatic; (k) m is 1; and (l) stereochemicalconfigurations depicted at asterisked positions indicate absolutestereochemistry.
 5. The compound of claim 4, characterized by formula(III):

or a pharmaceutically acceptable salt thereof, wherein Q is ═N— or═C(R^(k))—.
 6. The compound of claim 5, wherein: R^(g) is -V¹-T¹-R^(2g),-V¹—R^(1g), -T¹-R^(2g), or -T¹-V¹-R^(1g); V¹ is —C(R⁵)═C(R⁵), —C≡C—,—O—, —S—, or —N(R⁴)—; T¹ is a C₁₋₄ alkylene chain optionally substitutedwith one or two groups independently selected from fluoro or a C₁₋₄aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with one or twosubstituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y));and R^(1g) is an optionally substituted mono- or bicyclic aryl,heteroaryl, heterocyclyl, or cycloaliphatic group.
 7. The compound ofclaim 6, characterized by formula (V):

 or a pharmaceutically acceptable salt thereof, wherein: V¹ is —N(R⁸)—,—O—, or —S—; R⁸ is hydrogen or C₁₋₄ aliphatic; T¹ is a C₁₋₄ alkylenechain optionally substituted with one or two groups independentlyselected from fluoro or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with one or two substituents independentlyselected from the group consisting of —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)); and Ring C is a 3- to 8-memberedheterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl orheteroaryl ring, any of which rings is substituted with 0-2 R^(o) and0-2 R^(8o); each R^(o) independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵,—CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substitutedaliphatic, or an optionally substituted aryl, heterocyclyl, orheteroaryl group; or two R^(o) on the same saturated ring carbon atom,taken together with the carbon atom, form an optionally substituted 3-to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or twoadjacent R^(o), taken together with the intervening ring atoms, form anoptionally substituted fused 4- to 8-membered aromatic or non-aromaticring having 0-3 ring heteroatoms selected from the group consisting ofO, N, and S; each R^(8o) independently is selected from the groupconsisting of C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, halo, —OR^(5x),—N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted; R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted, or an optionally substituted 5- or 6-memberedaryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y), takentogether with the nitrogen atom to which they are attached, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R^(5x) independently is hydrogen,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl orC₆₋₁₀ ar(C₁₋₄)alkyl.
 8. The compound of claim 7, wherein: T¹ is a C₁₋₂alkylene chain optionally substituted with one or two groupsindependently selected from fluoro or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)); and Ring Cis a C₃₋₆ cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any ofwhich is substituted with 0-2 R^(8o) and optionally is fused to anoptionally substituted benzene, dioxolane, or dioxane ring.
 9. Thecompound of claim 5, characterized by formula (VI):

 or a pharmaceutically acceptable salt thereof, wherein: T¹ is a C₁₋₄alkylene chain optionally substituted with one or two groupsindependently selected from fluoro or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)); and Ring Cis a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5- or6-membered aryl or heteroaryl ring, any of which rings is substitutedwith 0-2 R^(o) and 0-2 R^(8o); each R^(o) independently is halo, —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionallysubstituted aliphatic, or an optionally substituted aryl, heterocyclyl,or heteroaryl group; or two R^(o) on the same saturated ring carbonatom, taken together with the carbon atom, form an optionallysubstituted 3- to 8-membered spirocyclic cycloaliphatic or heterocyclylring; or two adjacent R^(o), taken together with the intervening ringatoms, form an optionally substituted fused 4- to 8-membered aromatic ornon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S; each R^(8o) independently is selected fromthe group consisting of C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, halo,—OR^(5x), —N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); R^(4x) ishydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the arylportion of which may be optionally substituted; R^(4y) is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of whichmay be optionally substituted, or an optionally substituted 5- or6-membered aryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y),taken together with the nitrogen atom to which they are attached, forman optionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R^(5x) independently is hydrogen,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl orC₆₋₁₀ ar(C₁₋₄)alkyl.
 10. The compound of claim 9, wherein: T¹ is a C₁₋₂alkylene chain optionally substituted with one or two groupsindependently selected from fluoro or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), and —C(O)N(R^(4x))(R^(4y)); and Ring Cis phenyl, which is substituted with 0-2 R^(8o) and optionally is fusedto an optionally substituted benzene, dioxolane, or dioxane ring. 11.The compound of claim 5, characterized by formula (VII):

 or a pharmaceutically acceptable salt thereof, wherein: V² is —N(R⁸)—,—O—, or —S—; R⁸ is hydrogen or C₁₋₄ aliphatic; and Ring D is anoptionally substituted mono-, bi-, or tricyclic ring system.
 12. Thecompound of claim 11, wherein Ring D is selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl,indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,bicycloheptanyl and bicyclooctanyl.
 13. (canceled)
 14. The compound ofclaim 12, wherein: each R^(p) independently is selected from the groupconsisting of halo, C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, —R^(1p),—R^(2p), -T²-R^(1p), and -T²-R^(2p); or two R^(p) on the same saturatedcarbon atom, taken together with the carbon atom to which they areattached, form an optionally substituted 3- to 6-membered spirocycliccycloaliphatic ring; T² is a C₁₋₆ alkylene chain optionally substitutedwith R^(3a) or R^(3b); each R^(1p) independently is an optionallysubstituted aryl, heteroaryl, or heterocyclyl group; and each R^(2p)independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶,—SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.
 15. The compound of claim 14,wherein Ring D is an optionally substituted indanyl, tetrahydronaphthyl,or chromanyl.
 16. The compound of claim 15, wherein: V¹ is —N(R⁸)—; RingD is selected from the group consisting of:

each R^(p) independently is selected from the group consisting of halo,—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)), ora C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y));each R^(8p) independently is selected from the group consisting offluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), provided that R^(8p) is other than —OR^(5x) or—N(R^(4X))(R^(4y)) when located at a position adjacent to a ring oxygenatom, and further provided that when two R^(8p) are attached to the samecarbon atom, one must be selected from the group consisting of fluoro,—CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)), and C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or two R^(8p)on the same carbon atom together form ═O or ═C(R^(5x))₂; or two R^(8p)on the same carbon atom are taken together with the carbon atom to whichthey are attached to form a 3- to 6-membered spirocyclic ring; s is 0,1, 2, 3, or 4; t is 0, 1, or
 2. 17. The compound of claim 5,characterized by formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein stereochemicalconfigurations depicted at asterisked positions indicate absolutestereochemistry.
 18. The compound of claim 17, characterized by formula(VIIIa):

 or a pharmaceutically acceptable salt thereof, wherein: R^(a) is —OH;R^(b) and R^(d) are each independently hydrogen, fluoro, or C₁₋₄aliphatic; R^(c) is hydrogen, fluoro, or —OR⁵; R⁸ is hydrogen or C₁₋₄aliphatic; each R^(p) independently is selected from the groupconsisting of fluoro, —OR⁵, —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); each R^(8p) independently is selected from thegroup consisting of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), provided that R^(8p) is other than —OR⁵ or—N(R^(4x))(R^(4y)) when located at a position adjacent to a ring oxygenatom, and further provided that when two R^(8p) are attached to the samecarbon atom, one must be selected from the group consisting of fluoro,—CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)), and C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or two R^(8p)on the same carbon atom together form ═O or ═C(R^(5x))₂; R^(4x) ishydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the arylportion of which may be optionally substituted; R^(4y) is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of whichmay be optionally substituted, or an optionally substituted 5- or6-membered aryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y),taken together with the nitrogen atom to which they are attached, forman optionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; each R^(5x) independently is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl orC₆₋₁₀ ar(C₁₋₄)alkyl; s is 0, 1, or 2; and t is 0, 1, or
 2. 19. Acompound of formula (IX), formula (X), formula (XI), or formula (XII):

 wherein: depicted stereochemical configurations indicate absolutestereochemistry; Ring A is selected from the group consisting of:

wherein one ring nitrogen atom in Ring A optionally is oxidized, R^(b)is selected from the group consisting of hydrogen, fluoro, C₁₋₄aliphatic, and C₁₋₄ fluoroaliphatic; R^(d) is selected from the groupconsisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; R^(e) is hydrogen or C₁₋₄ aliphatic; or R^(e), takentogether with one R^(f) and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; each R^(f) independently is hydrogen,fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic; or two R^(f), takentogether with the carbon atom to which they are attached, form a 3- to6-membered carbocyclic ring; or one R^(f) taken together with R^(e) andthe intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;R^(g) is hydrogen, halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴ ₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OC(O)N(R⁴), —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴),—C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵,—C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl; each R^(h) independentlyis hydrogen, halo, —CN, —OH, —O—(C₁₋₄ aliphatic), —NH₂, —NH—(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —SH, —S—(C₁₋₄ aliphatic), or anoptionally substituted C₁₋₄ aliphatic group; R^(j) is hydrogen, —OR⁵,—SR⁶, —N(R⁴)₂, or an optionally substituted aliphatic, aryl, orheteroaryl group; R^(k) is hydrogen, halo, —OR⁵, —SR⁶, —N(R⁴)₂, or anoptionally substituted C₁₋₄ aliphatic group; R^(aa) and R^(bb) are eachindependently hydrogen or a hydroxyl protecting group, or R^(aa) andR^(bb) together form a cyclic diol protecting group; R^(cc) is hydrogenor a hydroxyl protecting group; or R^(aa) and R^(cc) together form acyclic diol protecting group.
 20. (canceled)
 21. (canceled)
 22. Thecompound of claim 19, characterized by formula (Xa):

wherein Ar is an optionally substituted aryl group.
 23. The compound ofclaim 22, selected from the group consisting of:


24. (canceled)
 25. The compound of claim 19, characterized by formula(XIa) or (XIIa)

wherein Ar is an optionally substituted aryl group.
 26. The compound ofclaim 19, selected from the group consisting of:

wherein Ar is an optionally substituted aryl group.
 27. The compound ofclaim 19, selected from the group consisting of:

wherein R^(aa) and R^(cc) are each independently a hydroxyl protectinggroup, or R^(aa) and R^(cc) together form a cyclic diol protectinggroup.
 28. The compound of claim 19, selected from the group consistingof:

wherein R^(aa) and R^(bb) are each independently a hydroxyl protectinggroup.
 29. A pharmaceutical composition, comprising a compound of claim2, or a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable carrier.
 30. (canceled)
 31. A method of decreasing an E1enzyme activity in a sample, comprising contacting the sample with acompound of claim
 1. 32. (canceled)
 33. (canceled)
 34. A method fortreating cancer in a patient in need thereof, comprising administeringto the patient a compound of claim
 1. 35. The method of claim 34,wherein the cancer is lung cancer, colorectal cancer, ovarian cancer, ora hematological cancer.
 36. A method for treating an immune responsedisorder or vascular cell proliferation disorder in a patient in needthereof, comprising administering to the patient a compound of claim 1.